Download to the Directory of Services

DirectoryofServices
TestDictionary
Notetouser:
23™
Thisdirectoryofservicesandtestdictionaryisdesignedtoassisttheuserinlearningmoreaboutreveal genetictestingservices,testingmethodologyandthe
comprehensivelistofgenetictestingoffered.Foreachgene,theuserhasaccesstoinformationaboutthenormalfunctionofspecificgene,anyhealthconditions
resulting from mutations in a specific gene and health condition keywords. For comprehensive information about a specific gene, user may use the Table of
Contents to identify the location where a specific gene is discussed. To search this directory using a specific health condition keyword, user may use Index 1,
HealthConditionKeywordGlossary,toidentifyallpageswherethespecifichealthconditionisdiscussed.
1
2
23™
reveal
Genetictestingservices
reveal23™ is a product created by Foundation Laboratory in an effort to bridge the gap between consumers and high
quality genetic testing at an affordable cost. During the last 5 decades Foundation Laboratory has been focused on
deliveringhighqualityandcuttingedgetechnologytothousandsofprovidersandmillionsofpeople.
As the healthcare industry has constantly evolved towards a more proactive approach to wellness so has Foundation
Laboratory. Realizing that medically relevant genetic information is the key to proactive decision-making, Foundation
Laboratory developed state of the art genetic testing utilizing next generation sequencing (NGS). reveal23™ genetic
testing product line is designed to analyze genetic changes that are associated with common health conditions. The
subject genetic testing will consist of germline (hereditary, predisposition only) analysis and not genetic mutations
related to somatic (genetic changes related to active cancer related conditions) changes. Hereditary conditions are
passed down from generation to generation. A mutation within specific genes analyzed through reveal23™ testing
productlineshaveclinicallyrelevantassociationtogeneralincreasedlifetimeriskofgettingcancer.
ThetestinglinesarecategorizedunderMaleandFemaleconfigurationswiththefollowingdetails:
Men’sWellness
Men’sWellnessPlus
Women’sHereditaryBreastandOvarianCancel(HBOC)
Women’sWellness
Women’sWellnessPlus
TotalWellness(ApplicabletoMenandWomen)
Men’s Wellness is composed of a genetic testing profile to include 35 different genes. The subject panel provides
geneticinformationon35genesassociatedwithlung,colorectal,uterine,pancreas,prostate,liverandstomachcancers.
Men’s Wellness Plus is composed of genetic testing profile to include 72 different genes. The subject panel provides
genetic information on 72 genes associated with lung, colorectal, breast, uterine, pancreas, prostate, liver, stomach,
bladder,GI,leukemia,esophagus,melanoma,kidney,LynchandCowdensyndromes.
Women’sHereditaryBreastandOvarianCancel(HBOC)iscomposedofagenetictestingprofiletoinclude25different
genes.Thesubjectpanelprovidesgeneticinformationon25genesassociatedwithbreast,ovarian,LynchandCowden
syndromes.
Women’sWellnessiscomposedofagenetictestingprofiletoinclude35differentgenes.Thesubjectpanelprovides
genetic information on 35 genes associated with breast, ovarian, Lynch and Cowden syndromes, lung, colorectal,
uterine,andpancreas.
Women’sWellnessPlusiscomposedofgenetictestingprofiletoinclude75differentgenes.Thesubjectpanelprovides
genetic information on 75 genes associated with breast, ovarian, Lynch and Cowden syndromes, lung, colorectal,
uterine,pancreas,prostatestomach/GI,leukemia,endocrine,liver,esophagus,kidney,andmelanoma.
TotalWellnessiscomposedofgenetictestingprofiletoinclude94differentgenes.Thesubjectpanelprovidesgenetic
information on 94 genes associated with breast, ovarian, Lynch and Cowden syndromes, lung, colorectal, uterine,
pancreas, kidney, prostate stomach/GI, leukemia, endocrine, liver, esophagus, melanoma, bladder, bone, Fanconi
anemiaandnervoussystem.
3
reveal23™Testingtechnology
reveal23™ is committed to providing state-of-the art genetic testing to patients from all walks of life. reveal23™ utilizes
Illumina sequencers and assays to bring cutting edge Next Generation Sequencing (NGS) technology, which efficiently
andaccuratelytargetsgermlinegenesassociatedwithcancerdispositionstopatientsandproviders.Germlinemutations
play an important role in cancer risk and susceptibility. Illumina next-generation sequencing (NGS) technology uses
clonal amplification and sequencing by synthesis (SBS) chemistry to enable rapid, accurate sequencing. The process
simultaneously identifies DNA bases while incorporating them into a nucleic acid chain. Each base emits a unique
fluorescent signal as it is added to the growing strand, which is used to determine the order of the DNA sequence. A
highlyscalabletechnology,DNAsequencingcanbeappliedtosmall,targetedregionsortheentiregenomethrougha
varietyofmethods,enablingresearcherstoinvestigateandbetterunderstandhealthanddisease.NGScanbeusedto
sequence many samples concurrently for germline mutations, increasing both the number of genes covered and the
confidence in covering relevant genes. Targeted sequencing enables accurate identification of cancer-predisposing
variants, with reduced data analysis burdens and time to answer. All Illumina sequencing systems use proven
sequencing by synthesis (SBS) technology. SBS is the most widely adopted next-generation sequencing (NGS)
technology,producingmorethan90%ofglobalsequencingdata.*SBSdelivershighlyaccuratebase-by-basesequencing
androbustperformanceacrossthegenome.
Aswelearnmoreabouttherolegeneticvariantsplayincancerpredisposition,thescientificcommunitywillneedtobe
abletoevaluatethegenesinwhichthesevariantsliecomprehensively.Thisprocessisnowsimplerandfasterwiththe
TruSight Cancer Sequencing Panel. Developed in collaboration with experts in cancer genomics, the oligos specifically
targetgenesassociatedwithcancer.TheTruSightCancerSequencingPaneltargets94genessuspectedtoplayarolein
predisposing to cancer, including genes associated with both common (ei. breast, colorectal) and rare cancers. In
addition,thepanelincludes284SNPssuspectedtobeassociatedwithcancerthroughgenome-wideassociationstudies
(GWAS). Content selection was based on expert curation of the scientific literature and other high-quality resources.
TruSight Cancer features a highly optimized probe set that delivers comprehensive coverage of genes suspected to
indicateapredispositionforcancer,startingfromonly50ngofDNAinputandtargetsatotalof255kbofthehuman
genome. The 80-mer probes target libraries of approximately 500 bp (insert size of 300 bp), enriching 350–650 bases
centeredsymmetricallyaroundthemidpointoftheprobe.ThismeanscoverageofexonicandnoncodingDNAinexon-
anking regions, on average 50 bp. High-throughput genomic technologies enable screening of large sample numbers
quickly to find disease-related causal variants. Many single nucleotide polymorphisms (SNPs) and copy number
variations(CNVs)areassociatedwithdisease.Causalvariantidentificationcanleadtofurtherstudiesofgenetargetsto
characterize disease mechanisms. These surveys can generate statistically significant disease associations and identify
potentialcausalvariantsofinterestforfuturestudies.Afterageneticvariantisassociatedwithadisease,furtherstudy
canrevealitseffectsongeneexpressionand/orregulation.
*Datacalculationsonfile.Illumina,Inc.2015
4
Gene: AIP (aryl hydrocarbon receptor interacting protein)
Normal function
The AIP gene provides instructions for making a protein called aryl hydrocarbon receptor-interacting protein (AIP). Although AIP's
function is not well understood, it is known to interact with numerous other proteins, including one called the aryl hydrocarbon
receptor. Through these interactions, AIP likely helps regulate certain cell processes, such as the growth and division (proliferation) of
cells, the process by which cells mature to carry out specific functions (differentiation), and cell survival. This protein is thought to act
as a tumor suppressor, which means it normally helps prevent cells from proliferating in an uncontrolled way.
Health conditions
Familial isolated pituitary adenoma (FIPA)
Mutations in the AIP gene cause 15 to 25 percent of cases of familial isolated pituitary adenoma (FIPA), an inherited condition
characterized by development of a noncancerous tumor in the pituitary gland (called a pituitary adenoma). This small gland at the base
of the brain produces hormones that control many important body functions. There are several types of pituitary adenomas categorized
by the hormone they produce. Affected individuals within the same family may develop the same type of pituitary adenoma or
different types. People with a mutation in the AIP gene most commonly develop a type of pituitary adenoma called a
somatotropinoma. FIPA tumors caused by AIP gene mutations usually occur at a younger age and are larger than those without AIP
gene mutations. Many kinds of mutations in the AIP gene have been identified in affected families. Some of these changes lead to an
abnormally short protein or no protein at all. Other mutations change single protein building blocks (amino acids) in AIP. Although it
is unclear how these mutations are involved in tumor development, researchers believe that the alterations disrupt interaction between
AIP and one or more other proteins. The ability of AIP to control cell proliferation may be reduced, allowing pituitary cells to grow
and divide unchecked and form a tumor. It is not known why the pituitary gland is specifically affected or why certain types of
pituitary adenomas develop. Even before FIPA was defined as a condition, doctors recognized that somatotropinomas could occur in
multiple members of a family. They referred to these tumors as isolated familial somatotropinoma. These tumors produce and release
excess growth hormone (also called somatotropin), which promotes growth of the body. Because it can cause overgrowth of the hands,
feet, and face (acromegaly), the condition is also referred to as familial isolated acromegaly. Later, researchers discovered that isolated
familial somatotropinoma can be caused by mutations in the AIP gene, and these tumors are now considered part of FIPA
Other disorders
Mutations in the AIP gene are found in a small percentage of individuals with sporadic macroadenomas, which are large (macro-)
pituitary adenomas that occur in individuals with no history of the condition in their family. When caused by AIP gene mutations, the
tumors occur at a relatively young age, usually before age 30. Although other family members are not affected, the gene mutation is
often inherited from a parent who never developed an adenoma.
Health condition keywords
Familial isolated pituitary adenoma (FIPA)
Isolated familial somatotropinoma
Familial isolated acromegaly
Sporadic macroadenomas
Gene: ALK (anaplastic lymphoma receptor tyrosine kinase)
Normal function
The ALK gene provides instructions for making a protein called anaplastic lymphoma kinase, part of a family of proteins called
receptor tyrosine kinases (RTKs). Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called
signal transduction. The process begins when the kinase is stimulated at the cell surface and then attaches to a similar kinase
(dimerizes). After dimerization, the kinase is tagged with a marker called a phosphate group (a cluster of oxygen and phosphorus
atoms) in a process called phosphorylation. Phosphorylation turns on (activates) the kinase. The activated kinase is able to transfer a
phosphate group to another protein inside the cell, which is activated as a result. The activation continues through a series of proteins
in a signaling pathway. These signaling pathways are important in many cellular processes such as cell growth and division
(proliferation) or maturation (differentiation).
Although the specific function of anaplastic lymphoma kinase is unknown, it is thought to act early in development to help regulate
the proliferation of nerve cells.
Health conditions
5
Lung cancer
Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung
cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells
when viewed under a microscope. Non-small cell lung cancer accounts for 85 percent of lung cancer, while small cell lung cancer
accounts for the remaining 15 percent.
Neuroblastoma
At least 16 mutations in the ALK gene have been identified in some people with neuroblastoma, a type of cancerous tumor composed
of immature nerve cells (neuroblasts). Neuroblastoma and Other disorders occur when a buildup of genetic mutations in critical
genes—those that control cell proliferation or differentiation—allows cells to grow and divide uncontrollably to form a tumor. In most
cases, these genetic changes are acquired during a person's lifetime and are called somatic mutations. Somatic mutations are present
only in certain cells and are not inherited. Less commonly, gene mutations that increase the risk of developing cancer can be inherited
from a parent. Both types of mutation occur in neuroblastoma. Somatic mutations in the ALK gene occur during the development of
some cases of sporadic neuroblastoma, and inherited mutations in the ALK gene increase the risk of developing familial
neuroblastoma. Mutations in the ALK gene change single protein building blocks (amino acids) in anaplastic lymphoma kinase. The
most common mutation in neuroblastoma replaces the amino acid arginine with the amino acid glutamine at position 1275 (written as
Arg1275Gln or R1275Q). Arg1275Gln has been found in both familial and sporadic neuroblastoma and is the only common ALK gene
mutation that has been found in both types of the condition. Occasionally, extra copies of the ALK gene are found in people with
neuroblastoma. This phenomenon, known as gene amplification, results in overexpression of anaplastic lymphoma kinase.
Mutated or overexpressed anaplastic lymphoma kinase no longer requires stimulation from outside the cell to be phosphorylated. As a
result, the kinase and the downstream signaling pathway are constantly turned on (constitutively activated). Constitutive activation of
anaplastic lymphoma kinase may increase the proliferation of immature nerve cells, leading to neuroblastoma.
Other disorder
Rearrangements of genetic material involving the ALK gene on chromosome 2 increase the risk of developing several other types of
cancer. These rearrangements are somatic mutations, which means they occur during a person's lifetime and are present only in the
cells that become cancerous. One type of rearrangement, called a translocation, exchanges genetic material between chromosome 2
and another chromosome. At least 15 translocations involving the ALK gene have been identified in people with anaplastic large cell
lymphoma (ALCL), a rare form of cancer involving immune cells called T cells. The most common translocation in ALCL occurs
between chromosome 2 and chromosome 5, called t(2;5). This translocation fuses the ALK gene to the NPM gene and results in a
fusion protein called NPM-ALK. In addition, at least seven translocations involving the ALK gene have been identified in
inflammatory myofibroblastic tumor (IMT). IMT is a rare cancer characterized by a solid tumor composed of inflammatory cells and
cells called myofibroblasts that are important in wound healing. About half of people with IMT have a translocation involving the
ALK gene. Another type of rearrangement, called an inversion, occurs when chromosome 2 is broken in two places and the resulting
piece of DNA is reversed and re-inserted into the chromosome. A small group of people with non-small cell lung cancer, the most
common type of lung cancer, have an inversion of chromosome 2. This inversion fuses the ALK gene with another gene called EML4
and results in the EML4-ALK fusion protein. The fusion proteins created by these rearranged genes have functions of both anaplastic
lymphoma kinase and the partner protein. The presence of the partner protein allows phosphorylation of anaplastic lymphoma kinase
without dimerization. The fusion protein and signaling pathways activated by anaplastic lymphoma kinase are constitutively activated,
which may abnormally increase the proliferation of immature nerve cells, leading to cancer formation.
Health condition keywords
Lung cancer
Neuroblastoma
Gene: APC (adenomatous polyposis coli)
Normal function
The APC gene provides instructions for making the APC protein, which plays a critical role in several cellular processes. The APC
protein acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. It
helps control how often a cell divides, how it attaches to other cells within a tissue, and whether a cell moves within or away from a
tissue. This protein also helps ensure that the number of chromosomes in a cell is correct following cell division. The APC protein
accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and
signaling. One protein with which APC associates is beta-catenin. Beta-catenin helps control the activity (expression) of particular
genes and promotes the growth and division (proliferation) of cells and the process by which cells mature to carry out specific
functions (differentiation). Beta-catenin also helps cells attach to one another and is important for tissue formation. Association of
APC with beta-catenin signals for beta-catenin to be broken down when it is no longer needed.
6
Health conditions
Desmoid tumor
Several mutations in the APC gene have been found in people with a type of aggressive but noncancerous (benign) growth called a
desmoid tumor. These rare tumors arise from connective tissue, which provides strength and flexibility to structures such as bones,
ligaments, and muscles. APC gene mutations typically cause formation of desmoid tumors in the abdomen, but these tumors can also
occur in other parts of the body. Although APC-related desmoid tumors are commonly associated with a form of colon cancer called
familial adenomatous polyposis (described below), APC gene mutations can cause tumors in individuals without this inherited disease.
APC gene mutations are found in about 10 to 15 percent of non-inherited (sporadic) desmoid tumors; these mutations are somatic,
which means they are acquired during a person's lifetime and are present only in tumor cells.
Most APC gene mutations that cause sporadic desmoid tumors lead to an abnormally short APC protein. The shortened protein is
unable to interact with the beta-catenin protein, which prevents the breakdown of beta-catenin when it is no longer needed. Excess
beta-catenin promotes uncontrolled growth and division of cells, allowing the formation of desmoid tumors.
Familial adenomatous polyposis
More than 700 mutations in the APC gene have been identified in families with the classic and attenuated types of familial
adenomatous polyposis (FAP). Most of these mutations lead to the production of an abnormally short, nonfunctional version of the
APC protein. This short protein cannot suppress the cellular overgrowth that leads to the formation of abnormal growths (polyps) in
the colon, which can become cancerous. The most common mutation in FAP is a deletion of five building blocks of DNA
(nucleotides) in the APC gene. This mutation changes the sequence of the building blocks of proteins (amino acids) in the resulting
APC protein. Although most people with FAP will develop colorectal cancer, the number of polyps and the time frame in which they
become cancerous depend on the location of the mutation in the APC gene. The location of the mutation also determines whether an
individual with FAP is predisposed to developing desmoid tumors (described above).
Primary macronodular adrenal hyperplasia
Primary macronodular adrenal hyperplasia (PMAH) is a disorder characterized by multiple lumps (nodules) in the adrenal glands,
which are small hormone-producing glands located on top of each kidney. These nodules, which usually are found in both adrenal
glands (bilateral) and vary in size, cause adrenal gland enlargement (hyperplasia) and result in the production of higher-than-normal
levels of the hormone cortisol. Cortisol is an important hormone that suppresses inflammation and protects the body from physical
stress such as infection or trauma through several mechanisms including raising blood sugar levels.
Other disorders
Mutations in the APC gene are also responsible for a disorder called Turcot syndrome, which is closely related to familial
adenomatous polyposis. Turcot syndrome is an association of colorectal cancer with a type of cancerous brain tumor called a
medulloblastoma. Approximately two-thirds of people with Turcot syndrome have mutations in the APC gene. A certain mutation in
the APC gene (unrelated to Turcot syndrome) is found in approximately 6 percent of people with Ashkenazi (eastern and central
European) Jewish heritage. This mutation replaces the amino acid isoleucine with the amino acid lysine at position 1307 in the APC
protein (written as Ile1307Lys or I1307K). This change was initially thought to be harmless, but has been shown to be associated with
a 10 percent to 20 percent increased risk of colon cancer. Somatic mutations in the APC gene may be involved in the development of a
small percentage of stomach (gastric) cancers.
Health condition keywords
Colorectal cancer
Desmoid tumor
Medulloblastoma
Primary macronodular adrenal hyperplasia
Turcot syndrome
Gene: ATM (ATM serine/threonine kinase)
Normal function
The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the
rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body
systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or
broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur
naturally when chromosomes exchange genetic material during cell division. The ATM protein coordinates DNA repair by activating
enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic
information. Because of its central role in cell division and DNA repair, the ATM protein is of great interest in cancer research.
7
Health conditions
Ataxia-telangiectasia
Researchers have identified several hundred mutations in the ATM gene that cause ataxia-telangiectasia. People with this disorder have
mutations in both copies of the ATM gene in each cell. Most of these mutations disrupt protein production, resulting in an abnormally
small, nonfunctional version of the ATM protein. Cells without any functional ATM protein are hypersensitive to radiation and do not
respond normally to DNA damage. Instead of activating DNA repair, the defective ATM protein allows mutations to accumulate in
other genes, which may cause cells to grow and divide in an uncontrolled way. This kind of unregulated cell growth can lead to the
formation of cancerous tumors. In addition, ATM mutations can allow cells to die inappropriately, particularly affecting cells in a part
of the brain involved in coordinating movements (the cerebellum). This loss of brain cells causes the movement problems
characteristic of ataxia-telangiectasia.
Breast cancer
Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although
breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most
common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands
that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. A small percentage
of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations.
Hereditary breast cancers tend to develop earlier in life than non-inherited (sporadic) cases, and new (primary) tumors are more likely
to develop in both breasts.
Other disorders
Research suggests that people who carry one mutated copy of the ATM gene in each cell may have an increased risk of developing
several other types of cancer. In particular, some studies have shown that cancers of the breast, stomach, bladder, pancreas, lung, and
ovaries occur more frequently in ATM mutation carriers than in people who do not carry these mutations. The results of similar
studies, however, have been conflicting. Additional research is needed to clarify which other types of cancer, if any, are associated
with ATM mutations.
Health condition keywords
Ataxia-telangiectasia
Bladder cancer
Breast cancer
Hereditary breast and ovarian cancer (HBOC)
Ovarian cancer
Lung cancer
Pancreatic cancer
Gene: BAP1 (BRCA1 associated protein 1)
Normal function
This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of
ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger
domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation
of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with
tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma
and cutaneous melanoma. [provided by RefSeq, May 2013]1
Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1. Catalytic
component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys119' (H2AK119ub1). Does not deubiquitinate monoubiquitinated histone H2B. Acts as a regulator of cell growth by mediating
deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains
compared to 'Lys-63'-linked polyubiquitin chains. Deubiquitination of HCFC1 does not lead to increase stability of HCFC1. Interferes
with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination. It
however does not mediate deubiquitination of BRCA1 and BARD1. Able to mediate autodeubiquitination via intramolecular
interactions to counteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic
sequestration (PubMed:24703950). Acts as a tumor suppressor. 2
8
Health conditions
Tumor predisposition syndrome
Tumor predisposition syndrome (TPDS): A condition characterized by predisposition to develop a variety of tumors, including benign
melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma
on exposure to asbestos, lung adenocarcinoma and meningioma. [MIM:614327] 2
Mesothelioma, malignant
An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindleshaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to
asbestos. [MIM:156240] 2
Health condition keywords
Cutaneous melanoma
Mesothelioma
Tumor predisposition syndrome
Uveal melanoma
Gene: BLM (Bloom syndrome RecQ like helicase)
Normal function
The BLM gene provides instructions for making a member of a protein family called RecQ helicases. Helicases are enzymes that
attach (bind) to DNA and unwind the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for several
processes in the cell nucleus, including copying (replicating) DNA in preparation for cell division and repairing damaged DNA.
Because RecQ helicases help maintain the structure and integrity of DNA, they are known as the "caretakers of the genome." When a
cell prepares to divide to form two cells, the DNA that makes up the chromosomes is copied so that each new cell will have two
copies of each chromosome, one from each parent. The copied DNA from each chromosome is arranged into two identical structures,
called sister chromatids, which are attached to one another during the early stages of cell division. Sister chromatids occasionally
exchange small sections of DNA during this time, a process called sister chromatid exchange. Researchers suggest that these
exchanges may be a response to DNA damage during the copying process. The BLM protein helps to prevent excess sister chromatid
exchanges and is also involved in other processes that help maintain the stability of the DNA during the copying process.
Health conditions
Bloom syndrome
More than 70 BLM gene mutations have been identified in people with Bloom syndrome, an inherited disorder characterized by short
stature, a skin rash that develops after exposure to the sun, and a greatly increased risk of cancer. One particular BLM gene mutation
causes almost all cases of Bloom syndrome among people of Central and Eastern European (Ashkenazi) Jewish descent. This
mutation deletes six DNA building blocks (nucleotides) and replaces them with seven others at position 2281 (written as 2281 delta
6ins7, or blmAsh). The blmAsh mutation results in the production of an abnormally short, nonfunctional version of the BLM protein.
Other BLM gene mutations change single protein building blocks (amino acids) in the protein sequence or create a premature stop
signal in the instructions for making the protein. These mutations also reduce the amount of functional BLM protein.
As a result of the lack of functional BLM protein, the frequency of sister chromatid exchange is about 10 times higher than average.
Exchange of DNA between chromosomes derived from the individual's mother and father are also increased in people with BLM gene
mutations. In addition, chromosome breakage occurs more frequently in affected individuals. All of these changes are associated with
gaps and breaks in the genetic material that impair normal cell activities and cause the health problems associated with this condition.
Without the BLM protein, the cell is less able to repair DNA damage caused by ultraviolet light, which results in increased sun
sensitivity. Genetic changes that allow cells to divide in an uncontrolled way lead to the cancers that occur in people with Bloom
syndrome.
Health condition keywords
Bloom syndrome
Gene: BMPR1A (bone morphogenetic protein receptor type 1A)
Normal function
The BMPR1A gene provides instructions for making a protein called bone morphogenetic protein receptor 1A. This receptor protein
has a specific site into which certain other proteins, called ligands, fit like keys into locks. Specifically, the BMPR1A protein attaches
9
(binds) to ligands in the transforming growth factor beta (TGF-β) pathway. This signaling pathway allows the environment outside the
cell to affect how the cell produces other proteins. The BMPR1A receptor protein and its ligands are involved in transmitting chemical
signals from the cell membrane to the nucleus. When the BMPR1A protein is bound to a ligand, it turns on (activates) a group of
related proteins (a protein complex) called SMAD proteins. The activated SMAD protein complex is then transported into the cell's
nucleus, where it regulates cell growth and division (proliferation) and the activity of particular genes.
Health conditions
Juvenile polyposis syndrome
More than 60 mutations in the BMPR1A gene have been found to cause juvenile polyposis syndrome. Most BMPR1A gene mutations
result in the production of an abnormally short, nonfunctional protein. As a result, the BMPR1A protein cannot bind to ligands in the
TGF-β pathway. This disruption in binding interferes with the activation of the SMAD protein complex. This inactive complex is not
transported to the nucleus, where it is needed to regulate cell growth and the activity of certain genes. Unregulated cell growth can
lead to polyp formation in people with juvenile polyposis syndrome.
Health condition keywords
Juvenile polyposis syndrome
Gene: BRCA1 (breast cancer 1)
Normal function
The BRCA1 gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent
cells from growing and dividing too rapidly or in an uncontrolled way. The BRCA1 protein is involved in repairing damaged DNA. In
the nucleus of many types of normal cells, the BRCA1 protein interacts with several other proteins to mend breaks in DNA. These
breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes
exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA1 protein plays a critical role in
maintaining the stability of a cell's genetic information. Research suggests that the BRCA1 protein also regulates the activity of other
genes and plays an essential role in embryonic development. To carry out these functions, the BRCA1 protein interacts with many
other proteins, including other tumor suppressors and proteins that regulate cell division.
Health conditions
Breast cancer
Researchers have identified more than 1,800 mutations in the BRCA1 gene. Many of these mutations are associated with an increased
risk of breast cancer in both men and women, as well as several other types of cancer. These mutations are present in every cell in the
body and can be passed from one generation to the next. As a result, they are associated with cancers that cluster in families. However,
not everyone who inherits a mutation in the BRCA1 gene will develop cancer. Other genetic, environmental, and lifestyle factors also
contribute to a person's cancer risk.
Most BRCA1 gene mutations lead to the production of an abnormally short version of the BRCA1 protein or prevent any protein from
being made from one copy of the gene. As a result, less of this protein is available to help repair damaged DNA or fix mutations that
occur in other genes. As these defects accumulate, they can trigger cells to grow and divide uncontrollably to form a tumor.
Ovarian cancer
Many of the same BRCA1 gene mutations that increase the risk of breast cancer (described above) also increase the risk of ovarian
cancer. Families with these mutations are often said to be affected by hereditary breast and ovarian cancer syndrome. Women with
BRCA1 gene mutations have a 35 to 60 percent chance of developing ovarian cancer in their lifetimes, as compared with 1.6 percent in
the general population.
Prostate cancer
At least five inherited BRCA1 gene mutations have been found to increase the risk of prostate cancer. These mutations likely reduce
the BRCA1 protein's ability to repair DNA, allowing potentially damaging mutations to persist in various other genes. The
accumulation of damaging mutations can lead to the out-of-control cell growth and division that can cause a tumor to develop. Men
who carry a BRCA1 gene mutation that increases the risk of prostate cancer may also be at increased risk for Other disorders.
Other disorders
Inherited mutations in the BRCA1 gene also increase the risk of several other types of cancer, including pancreatic cancer and colon
cancer. These mutations impair the ability of the BRCA1 protein to help repair damaged DNA. As defects accumulate in DNA, they
can trigger cells to grow and divide without order to form a tumor. It is not clear why different individuals with BRCA1 mutations
10
develop cancers in different organs. Environmental factors that affect specific organs may contribute to the development of cancers at
particular sites.
Health condition keywords
Breast cancer
Colorectal cancer
Hereditary breast and ovarian cancer (HBOC)
Ovarian cancer
Pancreatic cancer
Prostate cancer
Gene: BRCA2 (breast cancer 2)
Normal function
The BRCA2 gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent
cells from growing and dividing too rapidly or in an uncontrolled way. The BRCA2 protein is involved in repairing damaged DNA. In
the nucleus of many types of normal cells, the BRCA2 protein interacts with several other proteins to mend breaks in DNA. These
breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes
exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA2 protein plays a critical role in
maintaining the stability of a cell's genetic information. Researchers suspect that the BRCA2 protein has additional functions within
cells. For example, the protein may help regulate cytokinesis, which is the step in cell division when the fluid surrounding the nucleus
(the cytoplasm) divides to form two separate cells. Researchers are investigating the protein's other potential activities.
Health conditions
Breast cancer
Researchers have identified more than 1,800 mutations in the BRCA2 gene. Many of these mutations are associated with an increased
risk of breast cancer in both men and women, as well as several other types of cancer. These mutations are present in every cell in the
body and can be passed from one generation to the next. As a result, they are associated with cancers that cluster in families. However,
not everyone who inherits a mutation in the BRCA2 gene will develop cancer. Other genetic, environmental, and lifestyle factors also
contribute to a person's cancer risk.
Most BRCA2 gene mutations lead to the production of an abnormally small, nonfunctional version of the BRCA2 protein from one
copy of the gene in each cell. As a result, less of this protein is available to help repair damaged DNA or fix mutations that occur in
other genes. As these defects accumulate, they can trigger cells to grow and divide uncontrollably to form a tumor.
Fanconi anemia
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical
abnormalities, organ defects, and an increased risk of certain cancers. More than half of people with Fanconi anemia have physical
abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or
café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi
anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and
other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped
eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the
reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile).
Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased
fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly). Individuals with Fanconi anemia have
an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors
of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with
Fanconi anemia is between 10 and 30 percent.
Ovarian cancer
Many of the same BRCA2 gene mutations that increase the risk of breast cancer (described above) also increase the risk of ovarian
cancer. Families with these mutations are often said to be affected by hereditary breast and ovarian cancer syndrome. Women with
BRCA2 gene mutations have an approximately 12 to 25 percent chance of developing ovarian cancer in their lifetimes, as compared
with 1.6 percent in the general population.
Prostate cancer
11
More than 30 inherited BRCA2 gene mutations have been found to increase the risk of prostate cancer. Men with these mutations are
also more likely to develop prostate cancer at an earlier age and may be at increased risk of having an aggressive form of the disease.
They may also be at increased risk for Other disorders.
BRCA2 gene mutations likely reduce the BRCA2 protein's ability to repair DNA, allowing potentially damaging mutations to persist
in various other genes. The accumulation of damaging mutations can lead to the out-of-control cell growth and division that can result
in development of a tumor.
Other disorders
Inherited mutations in the BRCA2 gene also increase the risk of several other types of cancer, including pancreatic cancer and an
aggressive form of skin cancer called melanoma. These mutations impair the ability of the BRCA2 protein to help repair damaged
DNA. As defects accumulate in DNA, they can trigger cells to grow and divide without order to form a tumor. It is not clear why
different individuals with BRCA2 mutations develop cancers in different organs. Environmental factors that affect specific organs may
contribute to the development of cancers at particular sites.
Health condition keywords
Breast cancer
Colorectal cancer
Hereditary breast and ovarian cancer (HBOC)
Fanconi anemia
Melanoma
Ovarian cancer
Pancreatic cancer
Gene: BRIP1 (BRCA1 interacting protein C-terminal helicase 1)
Normal function
The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast
cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1
(BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]1
DNA-dependent ATPase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi
anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in
a manner that depends on its association with BRCA1.2
Health conditions
Breast cancer
A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern.
Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important
genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be
involved in different families or even in the same case. [MIM:114480] 2
Familial cancer of breast
A small percentage of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited
gene mutations. Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors
are more likely to develop in both breasts.
Fanconi anemia, complementation group J
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. [MIM:609054] 2
Fanconi anemia
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical
abnormalities, organ defects, and an increased risk of certain cancers. More than half of people with Fanconi anemia have physical
abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or
café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi
12
anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and
other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped
eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the
reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile).
Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased
fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly). Individuals with Fanconi anemia have
an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors
of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with
Fanconi anemia is between 10 and 30 percent.
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result.
Health condition keywords
Breast cancer
Familial cancer of breast
Fanconi anemia
Fanconi anemia, complementation group J
Hereditary breast and ovarian cancer (HBOC)
Ovarian cancer
Tracheoesophageal fistula
Gene: BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B)
Normal function
This gene encodes a kinase involved in spindle checkpoint function. The protein has been localized to the kinetochore and plays a role
in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper
chromosome segregation. Impaired spindle checkpoint function has been found in many forms of cancer. [provided by RefSeq, Jul
2008]1
Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until
all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphasepromoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other
is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE.
Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering
apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression. 2
Health conditions
Mosaic variegated aneuploidy syndrome
A severe developmental disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple
different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and
microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital
abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor and
leukemia reported in several cases. [MIM:257300] 2
13
Premature chromatid separation trait
Consists of separate and splayed chromatids with discernible centromeres and involves all or most chromosomes of a metaphase. It is
found in up to 2% of metaphases in cultured lymphocytes from approximately 40% of normal individuals. When PCS is present in 5%
or more of cells, it is known as the heterozygous PCS trait and has no obvious phenotypic effect, although some have reported
decreased fertility. Inheritance is autosomal dominant. [MIM:176430] 2
Health condition keywords
Mosaic variegated aneuploidy syndrome
Premature chromatid separation trait
Gene: CDC73 (cell division cycle 73)
Normal function
The CDC73 gene (also known as the HRPT2 gene) provides instructions for making a protein called parafibromin. This protein is
primarily found in the nucleus of cells and is likely involved in regulating gene transcription, which is the first step in protein
production. Parafibromin is also thought to play a role in cell growth and division (proliferation), either promoting or inhibiting cell
proliferation depending on signals within the cell. When parafibromin is found outside the nucleus, it appears to be involved in the
organization of the cell's structural framework (the cytoskeleton).
Health conditions
Familial isolated hyperparathyroidism
Inherited mutations in the CDC73 gene have been found in some families with familial isolated hyperparathyroidism, a condition
characterized by overactivity of the parathyroid glands (primary hyperparathyroidism). These glands release a hormone that helps
control the normal balance of calcium in the blood. Primary hyperparathyroidism disrupts this balance, which can lead to high blood
calcium levels (hypercalcemia), kidney stones, thinning of the bones (osteoporosis), nausea, vomiting, high blood pressure
(hypertension), weakness, and fatigue in people with familial isolated hyperparathyroidism. Primary hyperparathyroidism is a
characteristic feature of hyperparathyroidism-jaw tumor syndrome (described below); however, familial isolated hyperparathyroidism
is diagnosed in people with hyperparathyroidism but not the other features of hyperparathyroidism-jaw tumor syndrome. CDC73 gene
mutations that cause familial isolated hyperparathyroidism likely result in decreased activity of the parafibromin protein. Reduced
parafibromin activity can cause increased cell proliferation, leading to the formation of tumors involving the parathyroid glands.
Parathyroid tumors in people with familial isolated hyperparathyroidism are usually noncancerous. The resulting overactivity of the
parathyroid glands causes the signs and symptoms of the condition. The mutations associated with familial isolated
hyperparathyroidism are thought to have a less severe effect on protein function than those that cause hyperparathyroidism-jaw tumor
syndrome. Occasionally, individuals with familial isolated hyperparathyroidism later develop features of hyperparathyroidism-jaw
tumor syndrome, although some never do. Familial isolated hyperparathyroidism caused by CDC73 gene mutations may be an early or
mild form of hyperparathyroidism-jaw tumor syndrome.
Hyperparathyroidism-jaw tumor syndrome
More than 40 mutations in the CDC73 gene have been found to cause hyperparathyroidism-jaw tumor syndrome. Most of these
mutations result in a parafibromin protein that is abnormally short and nonfunctional. Without functional parafibromin, cell
proliferation is not properly regulated. Uncontrolled cell division resulting from the loss of parafibromin function can lead to the
formation of tumors in the parathyroid glands, jaw, uterus, and kidneys in people with hyperparathyroidism-jaw tumor syndrome.
Parathyroid tumors, which can be cancerous or noncancerous, interfere with the gland's normal function and lead to primary
hyperparathyroidism, a characteristic feature of hyperparathyroidism-jaw tumor syndrome.
Other disorders
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called
somatic mutations, are not inherited. Somatic changes in the CDC73 gene have been identified in many parathyroid cancers. These
mutations prevent parafibromin from effectively regulating cell proliferation, leading to uncontrolled cell growth and tumor
development. It is unclear why these mutations are associated with cancer in the parathyroid glands but not in other tissues in the
body.
Health condition keywords
Familial isolated hyperparathyroidism
Hyperparathyroidism-jaw tumor syndrome
14
Gene: CDH1 (cadherin 1)
Normal function
The CDH1 gene provides instructions for making a protein called epithelial cadherin or E-cadherin. This protein is found within the
membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body. E-cadherin belongs to a
family of proteins called cadherins whose function is to help neighboring cells stick to one another (cell adhesion) to form organized
tissues. E-cadherin is one of the best-understood cadherin proteins. In addition to its role in cell adhesion, E-cadherin is involved in
transmitting chemical signals within cells, controlling cell maturation and movement, and regulating the activity of certain genes. Ecadherin also acts as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an
uncontrolled way.
Health conditions
Breast cancer
Inherited mutations in the CDH1 gene increase a woman's risk of developing a form of breast cancer that begins in the milk-producing
glands (lobular breast cancer). In many cases, this increased risk occurs as part of an inherited cancer disorder called hereditary diffuse
gastric cancer (HDGC) (described below). Inherited mutations in the CDH1 gene are thought to account for only a small fraction of all
breast cancer cases. CDH1 gene mutations also occur commonly in lobular breast cancers in women without a family history of the
disease. These genetic changes, known as somatic mutations, are not inherited. Somatic gene mutations are acquired during a person's
lifetime and occur only in certain cells in the breast. Some of these genetic changes occur within the gene itself, while others turn off
(inactivate) a region of nearby DNA that controls the gene's activity. Researchers believe that the resulting loss of E-cadherin may
allow breast cells to grow and divide unchecked, leading to a cancerous tumor. A lack of this protein, which is critical for cell
adhesion, may also make it easier for cancer cells to detach from a primary tumor and spread (metastasize) to other parts of the body.
Hereditary diffuse gastric cancer
More than 120 inherited mutations in the CDH1 gene have been found to cause a familial cancer disorder called hereditary diffuse
gastric cancer (HDGC). People with CDH1 gene mutations associated with HDGC have an approximately 80 percent chance of
developing stomach (gastric) cancer in their lifetimes. Women with these mutations also have a 40 to 50 percent chance of developing
lobular breast cancer (described above). People with HDGC caused by CDH1 gene mutations are born with one mutated copy of the
gene in each cell. An additional mutation that impairs the normal copy of the CDH1 gene is needed for cancer to develop. This
mutation is a somatic mutation and is present only in cancer cells. The mutations that cause HDGC often lead to the production of an
abnormally short, nonfunctional version of the E-cadherin protein or lead to the production of a protein with an altered structure. The
loss of normal E-cadherin prevents it from acting as a tumor suppressor, contributing to the uncontrollable growth and division of
cells. A lack of E-cadherin impairs cell adhesion, increasing the likelihood that cancer cells will invade the stomach wall and small
clusters of cancer cells will metastasize into nearby tissues. In combination, the inherited and somatic mutations lead to a lack of
functional E-cadherin and result in HDGC.
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
Other disorders
Noninherited (somatic) CDH1 gene mutations are associated with an increased risk of other disorders, including cancers of the lining
of the uterus (endometrium) or the ovaries in women, and prostate cancer in men. These CDH1 gene mutations are thought to result in
a nonfunctional E-cadherin protein. A loss of functional E-cadherin in these cells prevents tumor suppression and cell adhesion,
leading to rapid cell growth and metastasis. It is unclear why CDH1 gene mutations affect certain tissues and not others.
15
Health condition keywords
Breast cancer
Hereditary breast and ovarian cancer (HBOC)
Hereditary diffuse gastric cancer
Ovarian cancer
Prostate cancer
Stomach cancer
Uterine cancer
Gene: CDK4 (cyclin-dependent kinase 4)
Normal function
The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products
of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1
phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type
cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene
product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to
be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by
RefSeq, Jul 2008]1
Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB)
protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the
transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for
the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major
integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and
represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation
and activity of the cyclin D-CDK4 complex.2
Health conditions
Cutaneous malignant melanoma 3
A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but
also may involve other sites. [MIM:609048] 2
Health condition keywords
Cutaneous malignant melanoma 3
Melanoma
Gene: CDKN1C (cyclin-dependent kinase inhibitor 1C)
Normal function
The CDKN1C gene provides instructions for making a protein that helps regulate growth. This protein acts as a tumor suppressor,
which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. It also is involved in controlling growth
before birth, preventing the developing fetus from becoming too large.
People inherit one copy of most genes from their mother and one copy from their father. Both copies are typically active, or "turned
on," in cells. However, the activity of the CDKN1C gene depends on which parent it was inherited from. In most tissues, the copy of
the gene inherited from a person's mother (the maternally inherited copy) has much higher activity than the copy inherited from the
father (the paternally inherited copy). This sort of parent-specific difference in gene activation is caused by a phenomenon called
genomic imprinting. CDKN1C is part of a cluster of genes on the short (p) arm of chromosome 11 that undergo genomic imprinting. A
nearby region of DNA known as imprinting center 2 (IC2) or KvDMR controls the parent-specific genomic imprinting of CDKN1C
and several other genes thought to help regulate growth. The IC2 region undergoes a process called methylation, which is a chemical
reaction that attaches small molecules called methyl groups to certain segments of DNA. Methylation, which occurs during the
formation of an egg or sperm cell, is a way of marking or "stamping" the parent of origin. The IC2 region is normally methylated only
on the maternally inherited copy of chromosome 11.
Health conditions
16
Bechwith-Wiedemann syndrome
Beckwith-Wiedemann syndrome is a condition that causes overgrowth and has other signs and symptoms that affect many parts of the
body. At least half of all cases of Beckwith-Wiedemann syndrome result from changes in methylation of the IC2 region. Specifically,
the maternally inherited copy of the IC2 region has too few methyl groups attached (hypomethylation). This abnormality disrupts the
regulation of several genes that are normally controlled by IC2, including CDKN1C. Because this gene normally restrains cell growth
and division, a reduction in its activity leads to overgrowth and the other features of Beckwith-Wiedemann syndrome. In a few cases,
Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the maternally inherited copy of the
IC2 region. Like abnormal methylation, these deletions disrupt the activity of several genes, including CDKN1C. BeckwithWiedemann syndrome can also result from mutations within the maternally inherited copy of the CDKN1C gene. More than two
dozen such mutations have been identified. Some of these genetic changes lead to an abnormally short, nonfunctional version of the
CDKN1C protein, while others alter single protein building blocks (amino acids) or delete a small number of amino acids from the
protein. All of these mutations are described as "loss-of-function" because they alter the structure of the CDKN1C protein such that it
can no longer control growth effectively. The resulting problems with growth regulation lead to overgrowth and the other features of
Beckwith-Wiedemann syndrome.
Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (IMAGe)
Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies, commonly known by the
acronym IMAGe, is a rare syndrome that affects the growth of many parts of the body. The condition is characterized by slow growth
before and after birth, skeletal abnormalities, hormonal changes, and genital abnormalities in males. At least six mutations in the
CDKN1C gene have been found to cause this condition. Because this gene is paternally imprinted, IMAGe syndrome results only
when the mutation is present on the maternally inherited copy of the gene. The CDKN1C gene mutations that cause IMAGe syndrome
replace single amino acids in a region known as the proliferating cell nuclear antigen (PCNA)-binding domain near the end of the
gene. These mutations appear to increase the stability of the CDKN1C protein, preventing it from being broken down normally. These
changes increase the amount of the protein that is available to restrain cell growth and division. Because these mutations enhance the
protein's usual function, they are described as "gain-of-function." The excess CDKN1C protein leads to IMAGe syndrome by
impairing normal growth and development starting before birth.
Health condition keywords
Beckwith-Wiedemann syndrome
Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (IMAGe)
Gene: CDKN2A (cyclin-dependent kinase inhibitor 2A)
Normal function
The CDKN2A gene provides instructions for making several proteins. The most well-studied are the p16(INK4a) and the p14(ARF)
proteins. Both function as tumor suppressors, which means they keep cells from growing and dividing too rapidly or in an
uncontrolled way. The p16(INK4a) protein attaches (binds) to two other proteins called CDK4 and CDK6. These proteins help
regulate the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion. CDK4 and CDK6 normally
stimulate the cell to continue through the cycle and divide. However, binding of p16(INK4a) blocks CDK4's or CDK6's ability to
stimulate cell cycle progression. In this way, p16(INK4a) controls cell growth and division. The p14(ARF) protein protects a different
protein called p53 from being broken down. The p53 protein is an important tumor suppressor that is essential for regulating cell
division and self-destruction (apoptosis). By protecting p53, p14(ARF) also helps prevent tumor formation.
Health conditions
Head and neck squamous cell carcinoma
Mutations in the CDKN2A gene are found in up to one-quarter of head and neck squamous cell carcinomas (HNSCC). This type of
cancerous tumor occurs in the moist lining of the mouth, nose, and throat. CDKN2A gene mutations associated with this condition are
acquired during a person's lifetime and are found only in tumor cells; these changes are known as somatic mutations. Most of these
mutations lead to production of little or no functional p16(INK4a) protein. Without p16(INK4a) to regulate cell growth and division,
cells can continue to grow and divide without control, which can lead to tumor formation. A different type of alteration involving the
CDKN2A gene can result in reduced amounts of the p16(INK4a) or p14(ARF) protein. This alteration, known as promoter
hypermethylation, turns off the production of p16(INK4a) or p14(ARF). Without one of these tumor suppressors, cells can grow and
divide unchecked, leading to the development of cancer.
Other disorders
Mutations affecting the CDKN2A gene are associated with other disorders, including a type of skin cancer called melanoma, breast
cancer, lung cancer, and pancreatic cancer. The mutations associated with these cancers are typically inherited (called germline
17
mutations) and are found in all cells in the body. In some families, CDKN2A gene mutations are associated with development of only
one type of cancer. In other families, mutations can lead to a cancer predisposition syndrome, which increases the risk of developing
multiple types of cancer. CDKN2A gene mutations involved in cancer impair production of functional p16(INK4a) or, less commonly,
p14(ARF), which can result in uncontrolled cell growth and tumor formation.
Health condition keywords
Breast cancer
Head and neck squamous cell carcinoma
Melanoma
Neuroblastoma
Pancreatic cancer
Gene: CEBPA (CCAAT/enhancer binding protein alpha)
Normal function
The CEBPA gene provides instructions for making a protein called CCAAT/enhancer-binding protein alpha. This protein is a
transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity (expression) of
certain genes. CCAAT/enhancer-binding protein alpha is involved in the maturation (differentiation) of certain blood cells. It is also
believed to act as a tumor suppressor, which means that it is involved in cellular mechanisms that help prevent the cells from growing
and dividing too rapidly or in an uncontrolled way.
Health conditions
Cytogenetically normal acute myeloid leukemia
Mutations in the CEBPA gene have been identified in some people with a form of acute myeloid leukemia known as cytogenetically
normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute
myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML. Mutations in this gene are
found in approximately 18 percent of individuals with CN-AML. When associated with CEBPA gene mutations, this condition can be
inherited, in which case it is called familial acute myeloid leukemia with mutated CEBPA (described above), or not inherited (sporadic
acute myeloid leukemia with mutated CEBPA). Two types of CEBPA gene mutations can occur in both the inherited and non-inherited
forms of CN-AML. One type leads to production of an abnormally short protein that interferes with the tumor suppressor function of
normal versions of CCAAT/enhancer-binding protein alpha. The other type of mutation blocks the DNA-binding ability of
CCAAT/enhancer-binding protein alpha. Impaired DNA binding interferes with the protein's ability to regulate gene expression and
impairs its tumor suppressor function. Impairment of the tumor suppressor function of CCAAT/enhancer-binding protein alpha leads
to the uncontrolled production of abnormal white blood cells that occurs in acute myeloid leukemia. Between 50 and 75 percent of all
individuals who have acute myeloid leukemia with mutations in the CEBPA gene, both sporadic and familial, have two mutated
CEBPA genes in each leukemia cell. The rest have only one CEBPA gene mutation. In the sporadic cases the mutation appears only in
the leukemia cells, and in the familial cases it is present throughout the body. Somatic mutations in other genes can also contribute to
the development of CN-AML.
Familial acute myeloid leukemia with mutated CEBPA
At least six mutations in the CEBPA gene have been identified in families with familial acute myeloid leukemia with mutated CEBPA,
which is a form of a blood cancer known as acute myeloid leukemia. These inherited mutations are present throughout a person's life
in virtually every cell in the body. The mutations result in a shorter version of CCAAT/enhancer-binding protein alpha. This shortened
protein is produced from one copy of the CEBPA gene in each cell, and it is believed to interfere with the tumor suppressor function of
the normal protein produced from the second copy of the gene. Absence of the tumor suppressor function of CCAAT/enhancerbinding protein alpha is believed to disrupt the regulation of blood cell production, leading to the uncontrolled production of abnormal
cells that occurs in acute myeloid leukemia. In addition to the inherited mutation in one copy of the CEBPA gene in each cell, most
individuals with familial acute myeloid leukemia with mutated CEBPA also acquire a mutation in the second copy of the CEBPA
gene. The additional mutation, which is called a somatic mutation, is found only in the cancerous leukemia cells and is not inherited.
The somatic CEBPA gene mutations that have been identified in leukemia cells generally decrease the DNA-binding ability of
CCAAT/enhancer-binding protein alpha. Researchers suggest that this second mutation may affect the normal differentiation of blood
cells, although exactly how the mutation is involved in the development of acute myeloid leukemia is unclear.
Health condition keywords
Cytogenetically normal acute myeloid leukemia
Familial acute myeloid leukemia with mutated CEBPA
18
Gene: CEP57 (centrosomal protein 57)
Normal function
This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular
stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the Cterminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts
with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates
the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic
distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell
division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple
alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]1
Centrosomal protein which may be required for microtubule attachment to centrosomes. May act by forming ring-like structures
around microtubules. Mediates nuclear translocation and mitogenic activity of the internalized growth factor FGF2, but that of FGF1.2
Health conditions
Mosaic variegated aneuploidy syndrome 2
A severe developmental disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple
different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and
microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital
abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor and
leukemia reported in several cases. [MIM:614114]2
Health condition keywords
Mosaic variegated aneuploidy syndrome 2
Gene: CHEK2 (checkpoint kinase 2)
Normal function
The CHEK2 gene provides instructions for making a protein called checkpoint kinase 2 (CHK2). This protein acts as a tumor
suppressor, which means that it regulates cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled
way. The CHK2 protein is activated when DNA becomes damaged or when DNA strands break. DNA can be damaged by agents such
as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, and breaks in DNA strands also occur naturally when
chromosomes exchange genetic material.
In response to DNA damage, the CHK2 protein interacts with several other proteins, including tumor protein 53 (which is produced
from the TP53 gene). These proteins halt cell division and determine whether a cell will repair the damage or self-destruct in a
controlled manner (undergo apoptosis). This process keeps cells with mutated or damaged DNA from dividing, which helps prevent
the development of tumors.
Health conditions
Breast cancer
Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although
breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most
common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands
that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. A small percentage
of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations.
Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors are more likely
to develop in both breasts.
Li-Fraumeni syndrome
Although most cases of Li-Fraumeni syndrome are associated with mutations in the TP53 gene, CHEK2 gene mutations have been
identified in several families with cancers characteristic of this condition. At least one family has a mutation that deletes a single DNA
building block (nucleotide) at position 1100 in the CHEK2 gene (written as 1100delC). The 1100delC mutation leads to the production
of an abnormally short, nonfunctional version of the CHK2 protein. Researchers are uncertain whether CHEK2 gene mutations
19
actually cause Li-Fraumeni syndrome or are merely associated with an increased risk of several types of cancer, including those
cancers often seen in LiOvarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
Other disorders
Mutations in the CHEK2 gene, including the 1100delC mutation described above have also been found in other hereditary and
nonhereditary (sporadic) cancers affecting many of the body's organs and tissues. Although the full range of cancers associated with
CHEK2 mutations has not been determined, studies have associated mutations in this gene with prostate, breast, lung, colon, kidney,
thyroid, and ovarian cancers. CHEK2 mutations have also been found in some brain tumors and in a type of bone cancer called
osteosarcoma.
Health condition keywords
Bone cancer
Brain cancer
Breast cancer
Colorectal cancer
Hereditary breast and ovarian cancer (HBOC)
Kidney cancer
Li-Fraumeni syndrome
Lung cancer
Ovarian cancer
Thyroid cancer
Gene: CYLD (CYLD lysine 63 deubiquitinase)
Normal function
The CYLD gene provides instructions for making a protein that helps regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a
group of related proteins that help protect cells from self-destruction (apoptosis) in response to certain signals. In regulating the action
of nuclear factor-kappa-B, the CYLD protein allows cells to respond properly to signals to self-destruct when appropriate, such as
when the cells become abnormal. By this mechanism, the CYLD protein acts as a tumor suppressor, which means that it helps prevent
cells from growing and dividing too fast or in an uncontrolled way.
Health conditions
Brooke-Spiegler syndrome
At least 20 CYLD gene mutations have been identified in individuals with Brooke-Spiegler syndrome. This condition is characterized
by multiple noncancerous (benign) tumors that develop in structures associated with the skin (skin appendages), such as sweat glands
and hair follicles. People with Brooke-Spiegler syndrome may develop several types of skin appendage tumors, including growths
called spiradenomas, trichoepitheliomas, and cylindromas. Spiradenomas are tumors of the sweat glands. Trichoepitheliomas arise
from the hair follicles. While previously thought to derive from sweat glands, cylindromas are now generally believed to begin in hair
follicles.
People with Brooke-Spiegler syndrome are born with a mutation in one of the two copies of the CYLD gene in each cell. This
mutation prevents the cell from making functional CYLD protein from the altered copy of the gene. However, enough protein is
20
usually produced from the other, normal copy of the gene to regulate cell growth effectively. For tumors to develop, a second mutation
or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's lifetime. These
genetic changes are called somatic mutations and are not inherited. When both copies of the CYLD gene are mutated in a particular
cell, that cell cannot produce any functional CYLD protein. The loss of this protein impairs the regulation of nuclear factor-kappa-B,
allowing the cell to grow and divide in an uncontrolled way to form a tumor. In people with Brooke-Spiegler syndrome, second CYLD
mutations typically occur in different types of cells in the skin over an affected person's lifetime, leading to the growth of multiple
types of skin appendage tumors.
Familial cylindromatosis
More than 30 CYLD gene mutations have been identified in individuals with familial cylindromatosis. People with this disorder
typically develop large numbers of cylindromas. As in Brooke-Spiegler syndrome, people with familial cylindromatosis are born with
one mutated copy of the CYLD gene in each cell, and a second mutation or deletion of genetic material involving the other copy of the
CYLD gene must occur in certain cells during a person's lifetime.
When both copies of the CYLD gene are mutated in particular hair follicle cells, those cells cannot produce any functional CYLD
protein. The loss of this protein allows the cells to grow and divide in an uncontrolled way to form cylindromas.
Multiple familial trichoepithelioma
At least 22 mutations in the CYLD gene have been identified in individuals with multiple familial trichoepithelioma. People with this
disorder typically develop large numbers of trichoepitheliomas. As in Brooke-Spiegler syndrome and familial cylindromatosis, people
with CYLD-related multiple familial trichoepithelioma are born with one mutated copy of the CYLD gene in each cell, and a second
mutation or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's
lifetime. When both copies of the CYLD gene are mutated in particular hair follicle cells, those cells cannot produce any functional
CYLD protein. The loss of this protein allows the cells to grow and divide in an uncontrolled way to form trichoepitheliomas. Some
researchers consider familial cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome to be different
forms of the same disorder. It is unclear why mutations in the CYLD gene cause different types of skin appendage tumors in each of
these conditions, or why the tumors are generally confined to the skin in these disorders.
Other disorders
Somatic mutations and reduced activity (expression) of the CYLD gene have also been identified in certain cancerous tumors. These
cancers include multiple myeloma, which starts in cells of the bone marrow, and cancers of the kidney, liver, uterus, and colon. These
genetic changes likely impair the tumor suppressor function of the CYLD protein, allowing cells to grow and divide in an uncontrolled
way and become cancerous.
Health condition keywords
Brooke-Spiegler syndrome
Familial cylindromatosis
Multiple familial trichoepithelioma
Gene: DDB2 (damage specific DNA binding protein 2)
Normal function
This gene encodes a protein that is necessary for the repair of ultraviolet light-damaged DNA. This protein is the smaller subunit of a
heterodimeric protein complex that participates in nucleotide excision repair, and this complex mediates the ubiquitylation of histones
H3 and H4, which facilitates the cellular response to DNA damage. This subunit appears to be required for DNA binding. Mutations
in this gene cause xeroderma pigmentosum complementation group E, a recessive disease that is characterized by an increased
sensitivity to UV light and a high predisposition for skin cancer development, in some cases accompanied by neurological
abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]1
Required for DNA repair. Binds to DDB1 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UVDDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER
pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4
photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as the substrate recognition module for the
DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB1-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4DDB-RBX1). The DDB1-CUL4-ROC1 complex may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced
DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair.
The DDB1-CUL4-ROC1 complex also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. Isoform D1
and isoform D2 inhibit UV-damaged DNA repair.2
21
Health conditions
Xeroderma pigmentosum complementation group E
An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for
developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling
and other pigmentation abnormalities. XP-E patients show a mild phenotype with minimal or no neurologic features. [MIM:278740]2
Health condition keywords
Xeroderma pigmentosum complementation group E
Gene: DICER1 (dicer 1, ribonuclease III)
Normal function
The DICER1 gene provides instructions for making a protein that plays a role in regulating the activity (expression) of other genes.
The Dicer protein aids in the production of a molecule called microRNA (miRNA). MicroRNAs are short lengths of RNA, a chemical
cousin of DNA. Dicer cuts (cleaves) precursor RNA molecules to produce miRNA. MicroRNAs control gene expression by blocking
the process of protein production. In the first step of making a protein from a gene, another type of RNA called messenger RNA
(mRNA) is formed and acts as the blueprint for protein production. MicroRNAs attach to specific mRNA molecules and stop the
process by which protein is made. Sometimes, miRNAs break down the mRNA, which also blocks protein production. Through this
role in regulating the expression of genes, Dicer is involved in many processes, including cell growth and division (proliferation) and
the maturation of cells to take on specialized functions (differentiation).
Health conditions
DICER1 syndrome
Mutations in the DICER1 gene cause DICER1 syndrome. People with this condition have an increased risk of developing many types
of tumors, particularly certain tumors of the lungs (pleuropulmonary blastoma); kidneys (cystic nephroma); ovaries (Sertoli-Leydig
tumors); and thyroid, a butterfly-shaped gland in the lower neck (multinodular goiter). Most of these mutations lead to an abnormally
short Dicer protein that is likely unable to produce miRNA. Without regulation by miRNA, genes are expressed abnormally, which
could cause cells to grow and divide uncontrollably and lead to tumor formation.
Health condition keywords
DICER1 syndrome
Kidney cancer
Lung cancer
Ovarian cancer
Gene: DIS3L2 (DIS3 like 3’-5’ exoribonuclease 2)
Normal function
The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large
multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some proteincoding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]1
3'-5'-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3' end and mediates their degradation. Component of
an exosome-independent RNA degradation pathway that mediates degradation of both mRNAs and miRNAs that have been
polyuridylated by a terminal uridylyltransferase, such as ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have
been deadenylated and subsequently uridylated at their 3'. Mediates degradation of uridylated pre-let-7 miRNAs, contributing to the
maintenance of embryonic stem (ES) cells. Essential for correct mitosis, and negatively regulates cell proliferation.2
Health conditions
Perlman syndrome
Perlman syndrome (PRLMNS): An autosomal recessive congenital overgrowth syndrome. Affected children are large at birth, are
hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set
eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent
neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor. Histologic
22
examination of the kidneys in affected children shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor.
[MIM:267000]2
Health condition keywords
Fetal gigantism
Perlman syndrome
Renal hamartomas nephroblastomatosis
Gene: EGFR (epidermal growth factor receptor)
Normal function
The EGFR gene provides instructions for making a receptor protein called the epidermal growth factor receptor, which spans the cell
membrane so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This
positioning allows the receptor to attach (bind) to other proteins, called ligands, outside the cell and to receive signals that help the cell
respond to its environment. Ligands and receptors fit together like keys into locks. Epidermal growth factor receptor binds to at least
seven different ligands. The binding of a ligand to an epidermal growth factor receptor allows the receptor to attach to a nearby
receptor protein (dimerize), turning on (activating) the receptor complex. As a result, signaling pathways within the cell are triggered
that promote cell growth and division (proliferation) and cell survival.
Health conditions
Lung Cancer
At least eight mutations in the EGFR gene have been associated with lung cancer, a disease in which certain cells in the lung become
abnormal and multiply uncontrollably to form a tumor. Nearly all these EGFR gene mutations occur during a person's lifetime
(somatic) and are only present in cancer cells. Other genetic, environmental, and lifestyle factors also contribute to a person's cancer
risk; in lung cancer, the greatest risk factor is being a long-term tobacco smoker. Somatic mutations in the EGFR gene most often
occur in a type of lung cancer called non-small cell lung cancer, specifically a form called adenocarcinoma. These mutations are most
common in people with the disease who have never smoked. Somatic EGFR gene mutations occur more frequently in Asian
populations with lung cancer than in affected white populations, occurring in 30 to 40 percent of affected Asians compared to 10 to 15
percent of whites with lung cancer. Most of the somatic EGFR gene mutations that are associated with lung cancer delete genetic
material in a part of the gene known as exon 19 or change DNA building blocks (nucleotides) in another region called exon 21. These
gene changes result in a receptor protein that is constantly turned on (constitutively activated), even when it is not bound to a ligand.
As a result, cells are signaled to constantly proliferate and survive, leading to tumor formation. When these gene changes occur in
cells in the lungs, lung cancer develops. Lung cancers with EGFR gene mutations tend to respond to treatments that target the
overactive signaling pathways that allow cancer cells to constantly grow and divide.
Health condition keywords
Lung cancer
Gene: EPCAM (epithelial cell adhesion molecule)
Normal function
The EPCAM gene provides instructions for making a protein known as epithelial cellular adhesion molecule (EpCAM). This protein is
found in epithelial cells, which are the cells that line the surfaces and cavities of the body. The EpCAM protein is found spanning the
membrane that surrounds epithelial cells, where it helps cells stick to one another (cell adhesion). In addition, the protein in the cell
membrane can be cut at a specific location, releasing a piece called the intracellular domain (EpICD), which helps relay signals from
outside the cell to the nucleus of the cell. EpICD travels to the nucleus and associates with other proteins, forming a group (complex)
that regulates the activity of several genes that are involved in cell growth and division (proliferation), maturation (differentiation),
and movement (migration), all of which are important processes for the proper development of cells and tissues.
Health conditions
Lynch syndrome
Certain mutations in the EPCAM gene are associated with Lynch syndrome, a condition that increases the risk of developing many
types of cancer, particularly cancers of the large intestine (colon) and the rectum (collectively called colorectal cancer). These
mutations account for up to 6 percent of Lynch syndrome cases. On chromosome 2, the EPCAM gene lies next to another gene called
MSH2. Each gene provides instructions for making an individual messenger RNA (mRNA), which serves as the genetic blueprint for
making the protein. The EPCAM gene mutations involved in Lynch syndrome remove a region that signals the end of the gene, which
23
leads to formation of a long mRNA that includes both EPCAM and MSH2. For unknown reasons, these EPCAM gene mutations cause
the MSH2 gene to be turned off (inactivated) by a mechanism known as promoter hypermethylation. The promoter is a region of DNA
near the beginning of the gene that controls gene activity (expression). Hypermethylation occurs when too many small molecules
called methyl groups are attached to the promoter region. The extra methyl groups attached to the MSH2 promoter reduce the
expression of the MSH2 gene, which means that less protein is produced in epithelial cells. The MSH2 protein plays an essential role
in repairing mistakes in DNA; loss of this protein prevents proper DNA repair, and mistakes accumulate as the cells continue to
divide. These mistakes can lead to uncontrolled cell growth and increase the risk of cancer
Other disorders
Mutations in the EPCAM gene can also cause congenital tufting enteropathy. This condition is characterized by abnormal
development of epithelial cells in the intestines. In this condition, the villi, which are small finger-like projections that line the small
intestine, are abnormal. In particular, they have "tufts" of extra epithelial cells on their tips. Normally, these projections provide a
greatly increased surface area to absorb nutrients. The altered villi are less able to absorb nutrients and fluids than normal tissue,
which causes life-threatening diarrhea and poor growth. Congenital tufting enteropathy develops in newborns within days of birth and
lasts throughout life. EPCAM gene mutations involved in this condition lead to the loss of functional EpCAM protein. The resulting
loss of EpICD signaling leads to abnormal development of intestinal epithelial cells, causing congenital tufting enteropathy.
Health condition keywords
Congenital tufting enteropathy
Lynch syndrome
Gene: ERCC2 (excision repair cross-complementation group2)
Normal function
The ERCC2 gene provides instructions for making a protein called XPD. This protein is an essential part (subunit) of a group of
proteins known as the general transcription factor IIH (TFIIH) complex. The TFIIH complex has two major functions: it is involved in
a process called gene transcription, and it helps repair damaged DNA.
Gene transcription is the first step in protein production. By controlling gene transcription, the TFIIH complex helps regulate the
activity of many different genes. The XPD protein appears to stabilize the TFIIH complex. Studies suggest that the XPD protein works
together with XPB, another protein in the TFIIH complex that is produced from the ERCC3 gene, to start (initiate) gene transcription.
The TFIIH complex also plays an important role in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from the
sun and by toxic chemicals, radiation, and unstable molecules called free radicals. DNA damage occurs frequently, but normal cells
are usually able to fix it before it can cause problems. One of the major mechanisms that cells use to fix DNA is known as nucleotide
excision repair (NER). As part of this repair mechanism, the TFIIH complex separates the section of double-stranded DNA that
surrounds the damage. The XPD protein helps with this process by acting as a helicase, which is an enzyme that attaches to particular
regions of DNA and temporarily unwinds the two spiral strands. Once the damaged region has been exposed, other proteins snip out
(excise) the abnormal section and replace the damaged area with the correct DNA.
Health conditions
Trichothiodystrophy
At least 20 mutations in the ERCC2 gene have been found to cause trichothiodystrophy. Mutations in this gene are the most common
cause of the photosensitive form of the condition, which is characterized by an extreme sensitivity to UV rays from sunlight. Studies
suggest that the ERCC2 gene mutations responsible for trichothiodystrophy reduce the amount of functional TFIIH complex in cells.
Without enough of this complex, cells cannot effectively repair DNA damage caused by UV radiation. These problems with DNA
repair cause people with the photosensitive form of trichothiodystrophy to be extremely sensitive to sunlight. Other features of the
condition, such as slow growth, intellectual disability, and brittle hair, probably result from problems with the transcription of genes
needed for normal development before and after birth. Unlike xeroderma pigmentosum (described below), trichothiodystrophy is not
associated with an increased risk of skin cancer. Researchers are working to determine why some mutations in the ERCC2 gene affect
a person's cancer risk and others do not.
Xeroderma pigmentosum
More than two dozen mutations in the ERCC2 gene have been identified in people with xeroderma pigmentosum. Mutations in this
gene are the second most common cause of xeroderma pigmentosum in the United States.
The ERCC2 gene mutations responsible for xeroderma pigmentosum prevent the TFIIH complex from repairing damaged DNA
effectively. As a result, abnormalities accumulate in DNA, causing cells to malfunction and eventually to become cancerous or die.
These problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays from sunlight.
When UV rays damage genes that control cell growth and division, cells can grow too fast and in an uncontrolled way. As a result,
24
people with xeroderma pigmentosum have a greatly increased risk of developing cancer. These cancers occur most frequently in areas
of the body that are exposed to the sun, such as the skin and eyes. When xeroderma pigmentosum is caused by ERCC2 gene
mutations, it is often associated with progressive neurological abnormalities. These nervous system problems include hearing loss,
poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing and talking, and
seizures. The neurological abnormalities are thought to result from a buildup of DNA damage, although the brain is not exposed to
UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma
pigmentosum develop neurological abnormalities and others do not.
Other disorders
Rarely, mutations in the ERCC2 gene can cause features of both xeroderma pigmentosum and trichothiodystrophy in the same
individual. This condition is known as xeroderma pigmentosum/trichothiodystrophy (XP/TTD) complex. ERCC2 gene mutations have
also been identified in a few individuals with signs and symptoms of both xeroderma pigmentosum and another condition related to
defective DNA repair called Cockayne syndrome. This combination of features is known as xeroderma pigmentosum/Cockayne
syndrome (XP/CS) complex. Researchers are uncertain how mutations in this single gene can cause several different disorders with a
wide variety of signs and symptoms. Studies suggest that different ERCC2 gene mutations affect the stability and function of the
TFIIH complex in different ways. Mutations also have varied effects on the interaction between the XPD protein and other proteins
that make up the TFIIH complex. These variations may account for the different features of xeroderma pigmentosum,
trichothiodystrophy, and XP/TTD and XP/CS complexes.
Health condition keywords
Trichothiodystrophy
Xeroderma pigmentosum
Gene: ERCC3 (excision repair cross-complementation group3)
Normal function
The ERCC3 gene provides instructions for making a protein called XPB. This protein is an essential part (subunit) of a group of
proteins known as the general transcription factor IIH (TFIIH) complex. The TFIIH complex has two major functions: it is involved in
a process called gene transcription, and it helps repair damaged DNA.
Gene transcription is the first step in protein production. By controlling gene transcription, the TFIIH complex helps regulate the
activity of many different genes. Studies suggest that the XPB protein works together with XPD, another protein in the TFIIH
complex that is produced from the ERCC2 gene, to start (initiate) gene transcription.
The TFIIH complex also plays an important role in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from the
sun and by toxic chemicals, radiation, and unstable molecules called free radicals. DNA damage occurs frequently, but normal cells
are usually able to fix it before it can cause problems. One of the major mechanisms that cells use to fix DNA is known as nucleotide
excision repair (NER). As part of this repair mechanism, the TFIIH complex unwinds the section of double-stranded DNA that
surrounds the damage. Studies suggest that the XPB protein may act as a wedge, holding open the two strands of DNA so other
proteins can snip out (excise) the abnormal section and replace the damaged area with the correct DNA.
Health conditions
Trichothiodystrophy
Trichothiodystrophy, which is commonly called TTD, is a rare inherited condition that affects many parts of the body. The hallmark
of this condition is brittle hair that is sparse and easily broken. Tests show that the hair is lacking sulfur, an element that normally
gives hair its strength. The signs and symptoms of trichothiodystrophy vary widely. Mild cases may involve only the hair. More
severe cases also cause delayed development, significant intellectual disability, and recurrent infections; severely affected individuals
may survive only into infancy or early childhood. About half of all people with trichothiodystrophy have a photosensitive form of the
disorder, which causes them to be extremely sensitive to ultraviolet (UV) rays from sunlight. They develop a severe sunburn after
spending just a few minutes in the sun. However, for reasons that are unclear, they do not develop other sun-related problems such as
excessive freckling of the skin or an increased risk of skin cancer. Many people with trichothiodystrophy report that they do not sweat.
Xeroderma pigmentosum
Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to
ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected
individuals also have problems involving the nervous system. People with xeroderma pigmentosum have a greatly increased risk of
developing skin cancer. Without sun protection, about half of children with this condition develop their first skin cancer by age 10.
Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. These cancers occur most often on the
face, lips, and eyelids. Cancer can also develop on the scalp, in the eyes, and on the tip of the tongue. Studies suggest that people with
25
xeroderma pigmentosum may also have an increased risk of other types of cancer, including brain tumors. Additionally, affected
individuals who smoke cigarettes have a significantly increased risk of lung cancer. About 30 percent of people with xeroderma
pigmentosum develop progressive neurological abnormalities in addition to problems involving the skin and eyes. These abnormalities
can include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty
swallowing and talking, and seizures. When these neurological problems occur, they tend to worsen with time. Researchers have
identified at least eight inherited forms of xeroderma pigmentosum: complementation group A (XP-A) through complementation
group G (XP-G) plus a variant type (XP-V). The types are distinguished by their genetic cause. All of the types increase skin cancer
risk, although some are more likely than others to be associated with neurological abnormalities.
Health condition keywords
Trichothiodystrophy
Xeroderma pigmentosum
Gene: ERCC4 (excision repair cross-complementation group 4)
Normal function
The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision
repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of
xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]1
Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair.
Involved in homologous recombination that assists in removing interstrand cross-link.2
Health conditions
Fanconi anemia complementation group Q
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. [MIM:615272] 2
Xeroderma pigmentosum
Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to
ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected
individuals also have problems involving the nervous system. People with xeroderma pigmentosum have a greatly increased risk of
developing skin cancer. Without sun protection, about half of children with this condition develop their first skin cancer by age 10.
Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. These cancers occur most often on the
face, lips, and eyelids. Cancer can also develop on the scalp, in the eyes, and on the tip of the tongue. Studies suggest that people with
xeroderma pigmentosum may also have an increased risk of other types of cancer, including brain tumors. Additionally, affected
individuals who smoke cigarettes have a significantly increased risk of lung cancer. About 30 percent of people with xeroderma
pigmentosum develop progressive neurological abnormalities in addition to problems involving the skin and eyes. These abnormalities
can include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty
swallowing and talking, and seizures. When these neurological problems occur, they tend to worsen with time. Researchers have
identified at least eight inherited forms of xeroderma pigmentosum: complementation group A (XP-A) through complementation
group G (XP-G) plus a variant type (XP-V). The types are distinguished by their genetic cause. All of the types increase skin cancer
risk, although some are more likely than others to be associated with neurological abnormalities.
Xeroderma pigmentosum complementation group F
An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for
developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling
and other pigmentation abnormalities. XP-F patients show a mild phenotype. [MIM:278760] 2
Xeroderma pigmentosum type F/Cockayne syndrome
A variant form of Cockayne syndrome, a disorder characterized by growth retardation, microcephaly, impairment of nervous system
development, pigmentary retinopathy, peculiar facies, and progeria together with abnormal skin photosensitivity. Cockayne syndrome
dermatological features are milder than those in xeroderma pigmentosum and skin cancers are not found in affected individuals.
26
XPF/CS patients, however, present with severe skin phenotypes, including severe photosensitivity, abnormal skin pigmentation, and
skin cancer predisposition. [MIM:278760] 2
XFE progeroid syndrome
A syndrome characterized by aged bird-like facies, lack of subcutaneous fat, dwarfism, cachexia and microcephaly. Additional
features include sun-sensitivity from birth, learning disabilities, hearing loss, and visual impairment. [MIM:610965] 2
Health condition keywords
Cockayne syndrome
Fanconi anemia complementation group Q
Tracheoesophageal fistula
Trichothiodystrophy
Xeroderma pigmentosum
Xeroderma pigmentosum group F
XFE progeroid syndrome
Gene: ERCC5 (excision repair cross-complementation group 5)
Normal function
This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UVinduced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and
transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is
also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased
susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is
characterized by severe growth defects, mental retardation, and cachexia. Read-through transcription exists between this gene and the
neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]1
Single-stranded structure-specific DNA endonuclease involved in DNA excision repair. Makes the 3'incision in DNA nucleotide
excision repair (NER). Acts as a cofactor for a DNA glycosylase that removes oxidized pyrimidines from DNA. May also be involved
in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too.2
Health conditions
Xeroderma pigmentosum
Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to
ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected
individuals also have problems involving the nervous system. People with xeroderma pigmentosum have a greatly increased risk of
developing skin cancer. Without sun protection, about half of children with this condition develop their first skin cancer by age 10.
Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. These cancers occur most often on the
face, lips, and eyelids. Cancer can also develop on the scalp, in the eyes, and on the tip of the tongue. Studies suggest that people with
xeroderma pigmentosum may also have an increased risk of other types of cancer, including brain tumors. Additionally, affected
individuals who smoke cigarettes have a significantly increased risk of lung cancer. About 30 percent of people with xeroderma
pigmentosum develop progressive neurological abnormalities in addition to problems involving the skin and eyes. These abnormalities
can include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty
swallowing and talking, and seizures. When these neurological problems occur, they tend to worsen with time. Researchers have
identified at least eight inherited forms of xeroderma pigmentosum: complementation group A (XP-A) through complementation
group G (XP-G) plus a variant type (XP-V). The types are distinguished by their genetic cause. All of the types increase skin cancer
risk, although some are more likely than others to be associated with neurological abnormalities.
Xeroderma pigmentosum complementation group G
An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for
developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling
and other pigmentation abnormalities. Some XP-G patients present features of Cockayne syndrome, cachectic dwarfism, pigmentary
retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne
syndrome traits is referred to as XP-CS complex. [MIM:278780] 2
Health condition keywords
Cockayne syndrome
27
Xeroderma pigmentosum
Xeroderma pigmentosum complementation group G
Gene: EXT1 (exostosin glycosyltransferase 1)
Normal function
The EXT1 gene provides instructions for producing a protein called exostosin-1. This protein is found in a cell structure called the
Golgi apparatus, which modifies newly produced enzymes and other proteins. In the Golgi apparatus, exostosin-1 attaches (binds) to
another protein, exostosin-2, to form a complex that modifies heparan sulfate. Heparan sulfate is a complex of sugar molecules (a
polysaccharide) that is added to proteins to form proteoglycans, which are proteins attached to several sugars. Heparan sulfate is
involved in regulating a variety of body processes including blood clotting and the formation of blood vessels (angiogenesis). It also
has a role in the spreading (metastasis) of cancer cells.
Health conditions
Hereditary multiple osteochondromas
About 460 mutations in the EXT1 gene have been identified in people with hereditary multiple osteochondromas type 1, a condition in
which people develop multiple benign (noncancerous) bone tumors called osteochondromas. Most of these mutations are known as
"loss-of-function" mutations because they prevent any functional exostosin-1 protein from being made. The loss of exostosin-1 protein
function prevents it from forming a complex with the exostosin-2 protein and adding heparan sulfate to proteins. It is unclear how this
impairment leads to the signs and symptoms of hereditary multiple osteochondromas.
Langer-Giedion syndrome
The deletion or mutation of the EXT1 gene and at least one additional gene on chromosome 8 causes Langer-Giedion syndrome. These
EXT1 gene mutations cause no exostosin-1 protein to be made. A lack of functional exostosin-1 protein causes the multiple benign
bone tumors (osteochondromas) seen in people with Langer-Giedion syndrome. People with Langer-Giedion syndrome are always
missing one functional copy of the EXT1 gene in each cell; however, other neighboring genes may also be involved. The deletion or
mutation of additional genes near the EXT1 gene likely contributes to the varied features of this condition.
Health condition keywords
Hereditary multiple osteochondromas
Langer-Giedion syndrome
Gene: EXT2 (exostosin glycosyltransferase 2)
Normal function
The EXT2 gene provides instructions for producing a protein called exostosin-2. This protein is found in a cell structure called the
Golgi apparatus, which modifies newly produced enzymes and other proteins. In the Golgi apparatus, exostosin-2 attaches (binds) to
another protein, exostosin-1, to form a complex that modifies a protein called heparan sulfate so it can be used in the body. Heparan
sulfate is involved in regulating a variety of body processes including the formation of blood vessels (angiogenesis) and blood
clotting. It also has a role in the spread (metastasis) of cancer cells.
Health conditions
Hereditary multiple osteochondromas
About 220 mutations in the EXT2 gene have been identified in people with hereditary multiple osteochondromas type 2, a condition in
which people develop multiple benign (noncancerous) bone tumors called osteochondromas. Most of these mutations prevent any
functional exostosin-2 protein from being made, and are called "loss-of-function" mutations. The loss of exostosin-2 protein function
prevents it from forming a complex with the exostosin-1 protein and modifying heparan sulfate. It is unclear how this impairment
leads to the development of multiple osteochondromas.
Potocki-Shaffer syndrome
A genetic change resulting in the deletion of the EXT2 gene causes a condition called Potocki-Shaffer syndrome. People with this
condition have multiple osteochondromas (described above) and enlarged openings in two bones that make up much of the top and
sides of the skull (enlarged parietal foramina). Other signs and symptoms seen in some people with Potocki-Shaffer syndrome include
intellectual disability, developmental delay, distinctive facial features, vision problems, and defects in the heart, kidneys, and urinary
tract. Potocki-Shaffer syndrome (sometimes referred to as proximal 11p deletion syndrome) is caused by a deletion of genetic material
from the short (p) arm of chromosome 11. In people with this condition, a loss of the EXT2 gene within this region is responsible for
28
multiple osteochondromas. The deletion likely leads to a reduction of exostosin-2 protein and the inability to process heparan sulfate
correctly. Although heparan sulfate is involved in many body processes, it is unclear how the lack of this protein causes multiple
osteochondromas. The loss of additional genes in the deleted region likely contributes to the other features of Potocki-Shaffer
syndrome. Specifically, loss of the ALX4 gene results in enlarged parietal foramina, and deletion of the PHF21A gene causes
intellectual disability and distinctive facial features.
Other disorders
At least two mutations in the EXT2 gene have been found in a family with seizures-scoliosis-macrocephaly syndrome. In individuals
with this condition, seizures typically begin in early childhood. Affected individuals also have an abnormal curvature of the spine
(scoliosis), an unusually large head (macrocephaly), intellectual disability, and weak muscle tone (hypotonia). The EXT2 gene
mutations associated with seizures-scoliosis-macrocephaly syndrome change single protein building blocks (amino acids) in the
exostosin-2 protein. These changes reduce the amount of functional exostosin-2 protein, which likely disrupts normal modification of
heparan sulfate. It is unclear how this disruption leads to the varied signs and symptoms of the condition. Individuals with seizuresscoliosis-macrocephaly syndrome do not appear to develop osteochondromas (described above).
Health condition keywords
Hereditary multiple osteochondromas
Potochi-Shaffer syndrome
Gene: EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit)
Normal function
The EZH2 gene provides instructions for making a type of enzyme called a histone methyltransferase. Histone methyltransferases
modify proteins called histones, which are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding
a molecule called a methyl group to histones (methylation), histone methyltransferases can turn off (suppress) the activity of certain
genes, an essential process in normal development. Specifically, the EZH2 enzyme forms part of a protein group called the polycomb
repressive complex-2. By turning off particular genes, this complex is involved in the process that determines the type of cell an
immature cell will ultimately become (cell fate determination).
Health conditions
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
Weaver syndrome
More than 30 EZH2 gene mutations have been identified in people with Weaver syndrome, which involves tall stature, a variable
degree of intellectual disability (usually mild), and characteristic facial features. These features can include a broad forehead; widely
spaced eyes (hypertelorism); large, low-set ears; a dimpled chin; and a small lower jaw (micrognathia). Some affected individuals
have a large head size (macrocephaly). Most of the EZH2 gene mutations associated with Weaver syndrome change single protein
building blocks (amino acids) in the EZH2 enzyme; others insert or delete small amounts of genetic material from the EZH2 gene,
leading to production of an altered EZH2 enzyme. It is unclear how these EZH2 gene mutations result in the abnormalities
characteristic of Weaver syndrome.
Other cancers
Changes in the EZH2 gene have been associated with various types of cancers. Mutations of this gene have been identified in cancers
of blood-forming tissues (lymphomas and leukemias). These mutations are described as "gain-of-function" because they appear to
enhance the activity of the EZH2 enzyme or give the enzyme a new, atypical function. In addition, excessive activity (overexpression)
of the EZH2 gene has been identified in cancerous tumors of the prostate, breast, and other parts of the body. Changes involving the
EZH2 gene likely impair normal control of cell division (proliferation), allowing cells to grow and divide too fast or in an uncontrolled
way and leading to the development of cancer.
Health condition keywords
Breast cancer
Prostate cancer
29
Weaver syndrome
Gene: FANCA (Fanconi anemia complementation group A)
Normal function
The FANCA gene provides instructions for making a protein that is involved in a cell process known as the Fanconi anemia (FA)
pathway. The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is
blocked due to DNA damage. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand crosslinks (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked
together, which stops the process of DNA replication. ICLs can be caused by a buildup of toxic substances produced in the body or by
treatment with certain cancer therapy drugs. The FANCA protein is one of a group of proteins known as the FA core complex. The FA
core complex is composed of eight FA proteins (including FANCA) and two proteins called Fanconi anemia-associated proteins
(FAAPs). This complex activates two proteins, called FANCD2 and FANCI, by attaching a single molecule called ubiquitin to each of
them (a process called monoubiquitination). The activation of these two proteins, which attach (bind) together to form the ID protein
complex, attract DNA repair proteins to the area of DNA damage so the error can be corrected and DNA replication can continue.
Health conditions
Fanconi anemia
More than 450 mutations in the FANCA gene have been found to cause Fanconi anemia, a disorder characterized by a decrease in
bone marrow function, an increased cancer risk, and physical abnormalities. Mutations in the FANCA gene are responsible for 60 to
70 percent of all cases of Fanconi anemia. These mutations change single DNA building blocks (nucleotides) or insert or delete pieces
of DNA in the FANCA gene. Some mutations allow production of a FANCA protein that has some residual function; other mutations
prevent the production of any FANCA protein. Mutations that prevent all protein production usually lead to a shortage of blood cells
at an earlier age and increase the risk of developing cancer of the blood-forming cells (leukemia) as compared to mutations that allow
for some FANCA protein production. Mutations in the FANCA gene lead to a nonfunctional FA core complex, which disrupts the
entire FA pathway. As a result, DNA damage is not repaired efficiently and ICLs build up over time. The ICLs stall DNA replication,
ultimately resulting in either abnormal cell death due to an inability make new DNA molecules or uncontrolled cell growth due to a
lack of DNA repair processes. Cells that divide quickly, such as bone marrow cells and cells of the developing fetus, are particularly
affected. The death of these cells results in the decrease in blood cells and the physical abnormalities characteristic of Fanconi anemia.
When the buildup of errors in DNA leads to uncontrolled cell growth, affected individuals can develop leukemia or other cancers.
Health condition keywords
Fanconi anemia
Gene: FANCB (Fanconi anemia complementation group B)
Normal function
This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein
complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL
syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]1
Health conditions
Fanconi anemia complementation group B
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. Some severe FANCB cases manifest features of VACTERL syndrome with hydrocephalus. [MIM:300514] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
30
Health condition keywords
Fanconi anemia
Fanconi anemia complementation group B
Tracheoesophageal fistula
Gene: FANCC (Fanconi anemia complementation group C)
Normal function
The FANCC gene provides instructions for making a protein that is involved in a cell process known as the Fanconi anemia (FA)
pathway. The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is
blocked due to DNA damage. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand crosslinks (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked
together, which stops the process of DNA replication. ICLs can be caused by a buildup of toxic substances produced in the body or by
treatment with certain cancer therapy drugs. The FANCC protein is one of a group of proteins known as the FA core complex. The FA
core complex is composed of eight FA proteins (including FANCC) and two proteins called Fanconi anemia-associated proteins
(FAAPs). This complex activates two proteins, called FANCD2 and FANCI, by attaching a single molecule called ubiquitin to each of
them (a process called monoubiquitination). The activation of these two proteins, which attach (bind) together to form the ID protein
complex, attract DNA repair proteins to the area of DNA damage so the error can be corrected and DNA replication can continue.
Health conditions
Fanconi anemia
At least 50 mutations in the FANCC gene have been found to cause Fanconi anemia, a disorder characterized by a decrease in bone
marrow function, an increased cancer risk, and physical abnormalities. Mutations in the FANCC gene are responsible for about 15
percent of all cases of Fanconi anemia. A particular mutation in the FANCC gene has been found in people with Central and Eastern
European (Ashkenazi) Jewish background. This mutation (written as 456+4A>T) disrupts the way the gene's instructions are used to
make the protein. Individuals with this mutation tend to have more severe signs and symptoms than people who have some of the
other mutations in the FANCC gene. Most mutations in the FANCC gene that cause Fanconi anemia lead to absent or reduced protein
function. As a result, the FA core complex cannot function and the entire FA pathway is disrupted. Due to the disrupted pathway,
DNA damage is not repaired efficiently and ICLs build up over time. The ICLs stall DNA replication, ultimately resulting in either
abnormal cell death due to an inability make new DNA molecules or uncontrolled cell growth due to a lack of DNA repair processes.
Cells that divide quickly, such as bone marrow cells and cells of the developing fetus, are particularly affected. The death of these
cells results in the decrease in blood cells and the physical abnormalities characteristic of Fanconi anemia. When the buildup of errors
in DNA leads to uncontrolled cell growth, affected individuals can develop leukemia or other cancers.
Health condition keywords
Fanconi anemia
Gene: FANCD2 (Fanconi anemia complementation group D2)
Normal function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2).
The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder
characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective
DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their
assembly into a common nuclear protein complex. This gene encodes the protein for complementation group D2. This protein is
monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2)
involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb
2016]1
Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in
the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. May participate in S phase
and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at
the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric
abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be
involved in B-cell immunoglobulin isotype switching.2
31
Health conditions
Fanconi anemia complementation group D2:
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. [MIM:227646] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Fanconi anemia
Fanconi anemia complementation group D2
Tracheoesophageal fistula
Gene: FANCE (Fanconi anemia complementation group E)
Normal function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2).
The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder
characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective
DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their
assembly into a common nuclear protein complex. This gene encodes the protein for complementation group E. [provided by RefSeq,
Jul 2008]1
As part of the Fanconi anemia (FA) complex functions in DNA cross-links repair. Required for the nuclear accumulation of FANCC
and provides a critical bridge between the FA complex and FANCD2.2
Health conditions
Fanconi anemia, complementation group E
Fanconi anemia complementation group E (FANCE): A disorder affecting all bone marrow elements and resulting in anemia,
leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a
predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging
agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. [MIM:600901] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Fanconi anemia
Fanconi anemia, complementation group E
Tracheoesophageal fistula
32
Gene: FANCF (Fanconi anemia complementation group F)
Normal function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2).
The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder
characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective
DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their
assembly into a common nuclear protein complex. This gene encodes the protein for complementation group F. [provided by RefSeq,
Jul 2008] 1
DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. May be implicated in interstrand
DNA cross-link repair and in the maintenance of normal chromosome stability. 2
Health conditions
Fanconi anemia, complementation group F
Fanconi anemia complementation group F (FANCF): A disorder affecting all bone marrow elements and resulting in anemia,
leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a
predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging
agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. [MIM:603467] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Fanconi anemia
Fanconi anemia, complementation group F
Tracheoesophageal fistula
Gene: FANCG (Fanconi anemia complementation group G)
Normal function
The FANCG gene provides instructions for making a protein that is involved in a cell process known as the Fanconi anemia (FA)
pathway. The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is
blocked due to DNA damage. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand crosslinks (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked
together, which stops the process of DNA replication. ICLs can be caused by a buildup of toxic substances produced in the body or by
treatment with certain cancer therapy drugs. The FANCG protein is one of a group of proteins known as the FA core complex. The FA
core complex is composed of eight FA proteins (including FANCG) and two proteins called Fanconi anemia-associated proteins
(FAAPs). This complex activates two proteins, called FANCD2 and FANCI, by attaching a single molecule called ubiquitin to each of
them (a process called monoubiquitination). The activation of these two proteins, which attach (bind) together to form the ID protein
complex, attracts DNA repair proteins to the area of DNA damage so the error can be corrected and DNA replication can continue.
Health conditions
Fanconi anemia
More than 50 mutations in the FANCG gene have been found to cause Fanconi anemia, a disorder characterized by a decrease in bone
marrow function, an increased cancer risk, and physical abnormalities. About 10 percent of all cases of Fanconi anemia are caused by
mutations in the FANCG gene. When Fanconi anemia results from mutations in this gene, it is often associated with a more severe
shortage of blood cells than when the condition is caused by mutations in other genes. Most mutations in the FANCG gene that cause
Fanconi anemia lead to absent or reduced protein function. Individuals who have mutations that lead to no protein production typically
have more severe signs or symptoms than people who have mutations that allow for some FANCG protein production. Due to a
33
decrease in FANCG protein function, the FA core complex cannot function and the entire FA pathway is disrupted. As a result, DNA
damage is not repaired efficiently and ICLs build up over time. The ICLs stall DNA replication, ultimately resulting in either
abnormal cell death due to an inability make new DNA molecules or uncontrolled cell growth due to a lack of DNA repair processes.
Cells that divide quickly, such as bone marrow cells and cells of the developing fetus, are particularly affected. The death of these
cells results in the decrease in blood cells and the physical abnormalities characteristic of Fanconi anemia. When the buildup of errors
in DNA leads to uncontrolled cell growth, affected individuals can develop leukemia or other cancers.
Health condition keywords
Fanconi anemia
Fanconi anemia complementation group G
Gene: FANCI (Fanconi anemia complementation group I)
Normal function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2).
The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder
characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective
DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their
assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing
results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]1
Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA
cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites.
Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and
double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.2
Health conditions
Fanconi anemia complementation group I
Fanconi anemia complementation group I (FANCI): A disorder affecting all bone marrow elements and resulting in anemia,
leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a
predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging
agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. [MIM:609053] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Fanconi anemia
Fanconi anemia complementation group I
Tracheoesophageal fistula
Gene: FANCL (Fanconi anemia complementation group L)
Normal condition
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2).
The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder
characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective
DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their
assembly into a common nuclear protein complex. This gene encodes the protein for complementation group L. Alternative splicing
results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008] 1
34
Ubiquitin ligase protein that mediates monoubiquitination of FANCD2, a key step in the DNA damage pathway. Also mediates
monoubiquitination of FANCI. May stimulate the ubiquitin release from UBE2W. May be required for proper primordial germ cell
proliferation in the embryonic stage, whereas it is probably not needed for spermatogonial proliferation after birth. 2
Health conditions
Fanconi anemia complementation group L
Fanconi anemia complementation group L (FANCL): A disorder affecting all bone marrow elements and resulting in anemia,
leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a
predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging
agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. [MIM:614083] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Fanconi anemia
Fanconi anemia complementation group L
Tracheoesophageal fistula
Gene: FANCM (Fanconi anemia complementation group M)
Normal function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2).
The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder
characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective
DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their
assembly into a common nuclear protein complex. This gene encodes the protein for complementation group M. Alternative splicing
results in multiple transcript variants. [provided by RefSeq, Apr 2015]1
ATPase required for FANCD2 ubiquitination, a key reaction in DNA repair. Binds to ssDNA but not to dsDNA. Recruited to forks
stalled by DNA interstrand cross-links, and required for cellular resistance to such lesions.2
Health conditions
Fanconi anemia
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical
abnormalities, organ defects, and an increased risk of certain cancers. More than half of people with Fanconi anemia have physical
abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or
café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi
anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and
other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped
eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the
reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile).
Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased
fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly). Individuals with Fanconi anemia have
an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors
of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with
Fanconi anemia is between 10 and 30 percent.
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
35
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition Keywords
Fanconi anemia
Fanconi anemia complementation group M
Tracheoesophageal fistula
Gene: FH (fumarate hydratase)
Normal function
The FH gene provides instructions for making an enzyme called fumarase (also known as fumarate hydratase). Fumarase participates
in an important series of reactions known as the citric acid cycle or Krebs cycle, which allows cells to use oxygen and generate
energy. Specifically, fumarase helps convert a molecule called fumarate to a molecule called malate.
Health conditions
Fumarase deficiency
Approximately 17 FH gene mutations that cause fumarase deficiency have been reported. Fumarase deficiency occurs in individuals
who inherit two mutated copies of the FH gene in each cell. Most of these mutations replace one protein building block (amino acid)
with another amino acid in the fumarase enzyme. These changes disrupt the ability of the enzyme to help convert fumarate to malate,
interfering with the function of this reaction in the citric acid cycle. Impairment of the process that generates energy for cells is
particularly harmful to cells in the developing brain, and this impairment results in the signs and symptoms of fumarase deficiency.
Hereditary leiomyomatosis and renal cell cancer
Approximately 50 mutations in the FH gene that cause hereditary leiomyomatosis and renal cell cancer (HLRCC) have been reported.
Most of these mutations replace one amino acid with another amino acid in the fumarase enzyme. People with HLRCC are born with
one mutated copy of the FH gene in each cell. The second copy of the FH gene in certain cells may also acquire mutations as a result
of environmental factors such as ultraviolet radiation from the sun or a mistake that occurs as DNA copies itself during cell division.
These changes are called somatic mutations and are not inherited. FH gene mutations may interfere with the enzyme's role in the citric
acid cycle, resulting in a buildup of fumarate. Researchers believe that the excess fumarate may interfere with the regulation of oxygen
levels in the cell. Chronic oxygen deficiency (hypoxia) in cells with two mutated copies of the FH gene may encourage tumor
formation and result in the tendency to develop leiomyomas and renal cell cancer.
Primary macronodular adrenal hyperplasia
Primary macronodular adrenal hyperplasia (PMAH) is a disorder characterized by multiple lumps (nodules) in the adrenal glands,
which are small hormone-producing glands located on top of each kidney. These nodules, which usually are found in both adrenal
glands (bilateral) and vary in size, cause adrenal gland enlargement (hyperplasia) and result in the production of higher-than-normal
levels of the hormone cortisol. Cortisol is an important hormone that suppresses inflammation and protects the body from physical
stress such as infection or trauma through several mechanisms including raising blood sugar levels.
Health condition keywords
Fumarase deficiency
Hereditary leiomyomatosis and renal cell cancer
Kidney cancer
Primary macronodular adrenal hyperplasia
Gene: FLCN (folliculin)
Normal function
The FLCN gene provides instructions for making a protein called folliculin. Researchers have not determined the protein's function,
but they believe it may act as a tumor suppressor. Tumor suppressors help control the growth and division of cells. The folliculin
protein is present in many of the body's tissues, including the brain, heart, placenta, testis, skin, lung, and kidney. Researchers have
proposed several possible roles for the protein within cells. Folliculin may be important for cells' uptake of foreign particles
(endocytosis or phagocytosis). The protein may also play a role in the structural framework that helps to define the shape, size, and
36
movement of a cell (the cytoskeleton) and in interactions between cells. In the lung, it is thought that folliculin plays a role in repairing
and re-forming lung tissue following damage.
Health conditions
Birt-Hogg-Dube syndrome
Several mutations in the FLCN gene have been identified in people with Birt-Hogg-Dubé syndrome, a condition characterized by
multiple noncancerous (benign) skin tumors, an increased risk of other tumors, and lung cysts. Most of these mutations insert or delete
one or more protein building blocks (amino acids) in the folliculin protein. These mutations lead to the production of an abnormally
small, nonfunctional version of this protein. Without folliculin, researchers believe that cells can grow and divide uncontrollably to
form cancerous or noncancerous tumors. They have not determined how a loss of folliculin increases the risk of lung abnormalities
that are often associated with Birt-Hogg-Dubé syndrome.
Primary spontaneous pneumothorax
At least eight mutations in the FLCN gene have been found to cause primary spontaneous pneumothorax. This condition occurs when
air builds up abnormally in the space between the lungs and the chest cavity (plural space), potentially leading to a partial or complete
collapse of the lung. Many of these mutations result in the production of a folliculin protein that is abnormally short and
nonfunctional. Researchers have not determined how FLCN gene mutations lead to the development of primary spontaneous
pneumothorax. One theory is that the altered folliculin protein may trigger inflammation within lung tissue that could lead to the
formation of small sacs of air (blebs) in the tissue. These blebs can rupture, causing air to leak into the pleural space. People who have
an FLCN gene mutation associated with primary spontaneous pneumothorax all appear to develop blebs, but it is estimated that only
40 percent of those individuals go on to have a primary spontaneous pneumothorax.
Other cancers
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, called somatic
mutations, are not inherited. Somatic mutations in the FLCN gene are probably associated with several types of nonhereditary
(sporadic) tumors. Specifically, somatic FLCN mutations have been identified in some cases of clear cell renal cell carcinoma (a type
of kidney cancer) and in some colon cancers. These mutations may change the structure of the folliculin protein, disrupting its tumor
suppressor function. Researchers do not know how FLCN mutations lead to these particular forms of cancer.
Health condition keywords
Birt-Hogg-Dube syndrome
Primary spontaneous pneumothorax
Gene: GATA2 (GATA binding protein 2)
Normal function
This gene encodes a member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide
sequence they bind in the promoter regions of target genes. The encoded protein plays an essential role in regulating transcription of
genes involved in the development and proliferation of hematopoietic and endocrine cell lineages. Alternative splicing results in
multiple transcript variants.[provided by RefSeq, Mar 2009]1
Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells. Binds to the consensus sequence 5'AGATAG-3'.2
Health conditions
Immunodeficiency 21
An immunodeficiency disease characterized by profoundly decreased or absent monocytes, B-lymphocytes, natural killer
lymphocytes, and circulating and tissue dendritic cells, with little or no effect on T-cell numbers. Clinical features of DCML include
susceptibility to disseminated non-tuberculous mycobacterial infections, papillomavirus infections, opportunistic fungal infections,
and pulmonary alveolar proteinosis. Bone marrow hypocellularity and dysplasia of myeloid, erythroid, and megakaryocytic lineages
are present in most patients, as are karyotypic abnormalities, including monosomy 7 and trisomy 8. This syndrome links susceptibility
to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.
[MIM:614172] 2
Lymphedema, primary, with myelodysplasia
37
A chronic disabling condition characterized by swelling of the extremities due to altered lymphatic flow, associated with
myelodysplasia. Patients with lymphedema suffer from recurrent local infections, and physical impairment. [MIM:614038] 2
Myelodysplastic syndrome
A heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular bone
marrow with impaired morphology and maturation, dysplasia of the myeloid, megakaryocytic and/or erythroid lineages, and
peripheral blood cytopenias resulting from ineffective blood cell production. Included diseases are: refractory anemia (RA), refractory
anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage
dysplasia and ringed sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative
disease. MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia
(AML). [MIM:614286] 2
Health condition keywords
Colorectal cancer
Dendritic cell, monocyte, B lymphocyte and natural killer lymphocyte deficiency
Immunodeficiency 21
Lymphedema, primary, with myelodysplasia
Myelodysplastic syndrome
Gene: GPC3 (glypican 3)
Normal function
The GPC3 gene provides instructions for making a protein called glypican 3. This protein is one of several glypicans in humans, each
of which consists of a core protein attached to long sugar molecules called heparan sulfate chains. Glypicans are anchored to the cell
membrane, where they interact with a variety of other proteins outside the cell. Glypicans appear to play important roles in
development before birth. These proteins are involved in numerous cell functions including regulating cell growth and division (cell
proliferation), cell survival, cell movement (migration), and the process by which cells mature to carry out specific functions
(differentiation). Several studies have found that glypican 3 interacts with other proteins at the surface of cells to restrain cell
proliferation. Researchers believe that in some cell types, glypican 3 may act as a tumor suppressor, which is a protein that prevents
cells from growing and dividing in an uncontrolled way to form a cancerous tumor. Glypican 3 may also cause some types of cells to
self-destruct (undergo apoptosis) when they are no longer needed, which can help keep growth in check.
Although glypican 3 is known primarily as an inhibitor of cell growth and cell division, in some tissues it appears to have the opposite
effect. Research suggests that in certain types of cells, such as cells in the liver, glypican 3 may interact with proteins called growth
factors to promote cell growth and cell division.
Health conditions
Simpson-Golabi-Behmel syndrome
More than 40 mutations in the GPC3 gene have been identified in people with Simpson-Golabi-Behmel syndrome. Some of these
mutations delete part or the entire gene, which prevents cells from producing functional glypican 3. Other mutations insert or delete a
small amount of genetic material in the GPC3 gene, or change one or a few protein building blocks (amino acids) used to make
glypican 3. These mutations change the structure of the protein.
Mutations in the GPC3 gene prevent glypican 3 from performing its usual functions, which may contribute to an increased rate of cell
proliferation starting before birth. It is unclear, however, how a shortage of functional glypican 3 leads to overgrowth of the entire
body and the other abnormalities characteristic of Simpson-Golabi-Behmel syndrome.
Other cancers
Changes in the activity (expression) of the GPC3 gene have been associated with several forms of cancer. In particular, this gene is
abnormally active (overexpressed) in a form of liver cancer called hepatocellular carcinoma. The increased gene expression may lead
to uncontrolled cell growth and cell division in liver cells, which can result in the development of a cancerous tumor. On the other
hand, a decrease in GPC3 gene expression has been found in some ovarian cancers, breast cancers, colon cancers, and mesotheliomas
(cancerous tumors that arise in the lining of the chest or abdomen).
Health condition keyword
Breast cancer
Liver cancer
Mesothelioma
Ovarian cancer
38
Simpson-Golabi-Behmel syndrome
Gene: HNF1A (HNF1 homebox A)
Normal function
The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded
protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of
maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing
results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]1
Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
Required for the expression of several liver specific genes. Binds to the inverted palindrome 5'-GTTAATNATTAAC-3'.2
Health conditions
Congenital hyperinsulinism
Congenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin, which is a hormone that
helps control blood sugar levels. People with this condition have frequent episodes of low blood sugar (hypoglycemia). In infants and
young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of
low blood sugar increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss,
brain damage, and coma. The severity of congenital hyperinsulinism varies widely among affected individuals, even among members
of the same family. About 60 percent of infants with this condition experience a hypoglycemic episode within the first month of life.
Other affected children develop hypoglycemia by early childhood. Unlike typical episodes of hypoglycemia, which occur most often
after periods without food (fasting) or after exercising, episodes of hypoglycemia in people with congenital hyperinsulinism can also
occur after eating.
Diabetes mellitus, insulin-dependent, 20
A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin
therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and
secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
[MIM:612520] 2
Type 1 diabetes
Hepatic adenomas, familial
Rare benign liver tumors of presumable epithelial origin that develop in an otherwise normal liver. Hepatic adenomas may be single or
multiple. They consist of sheets of well-differentiated hepatocytes that contain fat and glycogen and can produce bile. Bile ducts or
portal areas are absent. Kupffer cells, if present, are reduced in number and are non-functional. Conditions associated with adenomas
are insulin-dependent diabetes mellitus and glycogen storage diseases (types 1 and 3). [MIM:142330] 2
Maturity-onset diabetes of the young, type 3
Maturity-onset diabetes of the young 3 (MODY3): A form of diabetes that is characterized by an autosomal dominant mode of
inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent
insulin-independence at the beginning of the disease. [MIM:600496] 2
Health condition keywords
Congenital hyperinsulinism
Diabetes mellitus, insulin-dependent, 20
Diabetes mellitus type 1-2
Hepatic adenomas, familial
Maturity-onset diabetes of the young, type 3
Renal cell carcinoma, nonpapillary
Type 1 diabetes
Gene: HRAS (Harvey rat sarcoma viral oncogene homolog)
Normal function
The HRAS gene provides instructions for making a protein called H-Ras that is involved primarily in regulating cell division. Through
a process known as signal transduction, the H-Ras protein relays signals from outside the cell to the cell's nucleus. These signals
39
instruct the cell to grow or divide. The H-Ras protein is a GTPase, which means it converts a molecule called GTP into another
molecule called GDP. The H-Ras protein acts like a switch, and it is turned on and off by GTP and GDP molecules. To transmit
signals, the protein must be turned on by attaching (binding) to a molecule of GTP. The H-Ras protein is turned off (inactivated) when
it converts GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus. The HRAS gene belongs to a
class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The
HRAS gene is in the Ras family of oncogenes, which also includes two other genes: KRAS and NRAS. The proteins produced from
these three genes are GTPases. These proteins play important roles in cell division, the process by which cells mature to carry out
specific functions (cell differentiation), and the self-destruction of cells (apoptosis).
Health conditions
Bladder cancer
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called
somatic mutations, are not inherited. Somatic HRAS gene mutations that occur in bladder cells have been associated with some cases
of bladder cancer. A particular mutation has been identified in a significant percentage of bladder tumors; this mutation replaces the
amino acid glycine with the amino acid valine at protein position 12 (written as Gly12Val or G12V). As a result of this genetic
change, the altered H-Ras protein becomes continuously active within the cell. The overactive H-Ras protein directs the cell to grow
and divide abnormally, leading to uncontrolled cell division and the formation of a tumor. Mutations in the HRAS gene also have been
associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment.
Costello syndrome
At least 15 mutations in the HRAS gene have been identified in people with Costello syndrome, a rare condition that affects many
parts of the body and increases the risk of developing cancerous and noncancerous tumors. The mutations change single protein
building blocks (amino acids) in a critical region of the H-Ras protein. The most common mutation accounts for more than 80 percent
of all cases of Costello syndrome; it replaces the amino acid glycine with the amino acid serine at protein position 12 (written as
Gly12Ser or G12S). The HRAS gene mutations that cause Costello syndrome lead to the production of an H-Ras protein that is
abnormally turned on (active) in cells throughout the body. Instead of triggering cell growth in response to signals from outside the
cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of
noncancerous and cancerous tumors. Researchers are uncertain how mutations in the HRAS gene cause the other features of Costello
syndrome (such as intellectual disability, distinctive facial features, and heart problems), but many of the signs and symptoms
probably result from cell overgrowth and abnormal cell division.
Head and neck squamous cell carcinoma
Squamous cell carcinoma is a cancer that arises from particular cells called squamous cells. Squamous cells are found in the outer
layer of skin and in the mucous membranes, which are the moist tissues that line body cavities such as the airways and intestines.
Head and neck squamous cell carcinoma (HNSCC) develops in the mucous membranes of the mouth, nose, and throat. HNSCC is
classified by its location: it can occur in the mouth (oral cavity), the middle part of the throat near the mouth (oropharynx), the space
behind the nose (nasal cavity and paranasal sinuses), the upper part of the throat near the nasal cavity (nasopharynx), the voicebox
(larynx), or the lower part of the throat near the larynx (hypopharynx). Depending on the location, the cancer can cause abnormal
patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore
throat, earache, pain when swallowing or difficulty swallowing, a hoarse voice, difficulty breathing, or enlarged lymph nodes.
HNSCC can spread (metastasize) to other parts of the body, such as the lymph nodes or lungs. If it spreads, the cancer has a worse
prognosis and can be fatal. About half of affected individuals survive more than five years after diagnosis.
Other cancers
Somatic mutations in the HRAS gene are probably involved in the development of several additional types of cancer. These mutations
lead to a version of the H-Ras protein that is always active and can direct cells to grow and divide without control. Studies suggest that
HRAS gene mutations may be common in thyroid and kidney cancers. Increased activity (expression) of the HRAS gene has also been
reported in other types of cancer.
Health condition keywords
Bladder cancer
Costello syndrome
Head and neck squamous cell carcinoma
Kidney cancer
Thyroid cancer
40
Gene: KIT (KIT proto-oncogene receptor tyrosine kinase)
Normal function
The KIT gene provides instructions for making a protein that belongs to a family of proteins called receptor tyrosine kinases. Receptor
tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The KIT protein is
found in the cell membrane of certain cell types where a specific protein, called stem cell factor, attaches (binds) to it. This binding
turns on (activates) the KIT protein, which then activates other proteins inside the cell by adding a cluster of oxygen and phosphorus
atoms (a phosphate group) at specific positions. This process, called phosphorylation, leads to the activation of a series of proteins in
multiple signaling pathways. The signaling pathways stimulated by the KIT protein control many important cellular processes such as
cell growth and division (proliferation), survival, and movement (migration). KIT protein signaling is important for the development
of certain cell types, including reproductive cells (germ cells), early blood cells (hematopoietic stem cells), immune cells called mast
cells, cells in the gastrointestinal tract called interstitial cells of Cajal (ICCs), and cells called melanocytes. Melanocytes produce the
pigment melanin, which contributes to hair, eye, and skin color.
Health conditions
Core binding factor acute myeloid leukemia
Core binding factor acute myeloid leukemia (CBF-AML) is one form of a cancer of the blood-forming tissue (bone marrow) called
acute myeloid leukemia. In normal bone marrow, early blood cells called hematopoietic stem cells develop into several types of blood
cells: white blood cells (leukocytes) that protect the body from infection, red blood cells (erythrocytes) that carry oxygen, and platelets
(thrombocytes) that are involved in blood clotting. In acute myeloid leukemia, the bone marrow makes large numbers of abnormal,
immature white blood cells called myeloid blasts. Instead of developing into normal white blood cells, the myeloid blasts develop into
cancerous leukemia cells. The large number of abnormal cells in the bone marrow interferes with the production of functional white
blood cells, red blood cells, and platelets.
Gastrointestinal stromal tumor
Mutations in the KIT gene are the most common genetic changes associated with gastrointestinal stromal tumors (GISTs). GISTs are a
type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. In most cases, these KIT gene
mutations are acquired during a person's lifetime and are called somatic mutations. Somatic mutations, which lead to sporadic GISTs,
are present only in the tumor cells and are not inherited. Less commonly, KIT gene mutations that increase the risk of developing
GISTs are inherited from a parent, which can lead to familial GISTs. KIT gene mutations associated with GISTs create a protein that
no longer requires binding of the stem cell factor protein to be activated. As a result, the KIT protein and the signaling pathways are
constantly turned on (constitutively activated), which increases the proliferation and survival of ICCs, leading to GIST formation.
Piebaldism
At least 69 KIT gene mutations have been identified in people with piebaldism. This condition is characterized by white patches of
skin and hair caused by a lack of melanocytes. The mutations responsible for piebaldism lead to a nonfunctional KIT protein. The loss
of KIT signaling is thought to disrupt melanocyte migration and proliferation during development, resulting in patches of skin that
lack pigmentation.
Other cancers
Somatic mutations in the KIT gene have been identified in several cancers. KIT gene mutations are involved in some cases of acute
myeloid leukemia, which is a cancer of a type of blood cell known as myeloid cells, and sinonasal natural killer/T-cell lymphoma
(NKTCL), another blood cell cancer that occurs in the nasal passages. In addition, some people with seminoma, a type of testicular
cancer, have a KIT gene mutation. The genetic changes involved in acute myeloid leukemia and seminomas lead to a KIT protein that
is constitutively activated. The constant signaling causes overproliferation of the cells that make up these tumors. It is unclear how the
KIT mutations in NKTCL are involved in the condition.
Other disorders
KIT gene mutations are also involved in mastocytosis, which represents a group of related conditions. These conditions are
characterized by an overgrowth of mast cells, which are cells that trigger inflammation during an allergic reaction or an infection.
Accumulation of excess mast cells in the skin causes a condition called urticaria pigmentosa, and accumulation in additional organs
leads to systemic mastocytosis. The KIT gene mutations involved in this group of conditions lead to a constitutively activated KIT
protein, which causes the overgrowth of mast cells.
Health condition keywords
Core binding factor acute myeloid leukemia
Gastrointestinal stromal tumor
41
Piebaldism
Gene: MAX (MYC associated factor X)
Normal function
The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It
is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. Myc is an oncoprotein
implicated in cell proliferation, differentiation and apoptosis. The homodimers and heterodimers compete for a common DNA target
site (the E box) and rearrangement among these dimer forms provides a complex system of transcriptional regulation. Mutations of
this gene have been reported to be associated with hereditary pheochromocytoma. A pseudogene of this gene is located on the long
arm of chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]1
Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MYC or MAD which recognizes the core
sequence 5'-CAC[GA]TG-3'. The MYC:MAX complex is a transcriptional activator, whereas the MAD:MAX complex is a repressor.
May repress transcription via the recruitment of a chromatin remodeling complex containing H3 'Lys-9' histone methyltransferase
activity.2
Health conditions
Pheochromocytoma
Hereditary paraganglioma-pheochromocytoma is a condition characterized by the growth of noncancerous (benign) tumors in
structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. A tumor involving
the paraganglia is known as a paraganglioma. A type of paraganglioma known as a pheochromocytoma develops in the adrenal
glands, which are located on top of each kidney and produce hormones in response to stress. Other types of paraganglioma are usually
found in the head, neck, or trunk. People with hereditary paraganglioma-pheochromocytoma develop one or more paragangliomas,
which may include pheochromocytomas. Pheochromocytomas and some other paragangliomas are associated with ganglia of the
sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body
due to hormones released in response to stress. Sympathetic paragangliomas found outside the adrenal glands, usually in the abdomen,
are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called
catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such
as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating. Researchers have identified
four types of hereditary paraganglioma-pheochromocytoma, named types 1 through 4. Each type is distinguished by its genetic cause.
People with types 1, 2, and 3 typically develop paragangliomas in the head or neck region. People with type 4 usually develop extraadrenal paragangliomas in the abdomen and are at higher risk for malignant tumors that metastasize. Hereditary paragangliomapheochromocytoma is typically diagnosed in a person's 30s.
Health condition keyword
Pheochromocytoma
Gene: MEN1 (menin1)
Normal function
The MEN1 gene provides instructions for making a protein called menin. This protein acts as a tumor suppressor, which means that it
keeps cells from growing and dividing too fast or in an uncontrolled way. Although the exact function of menin is unclear, it is likely
involved in several important cell functions. For example, it may play a role in copying and repairing DNA and regulating the
controlled self-destruction of cells (apoptosis). The menin protein is present in the nucleus of many different types of cells and appears
to be active in all stages of development.
Menin interacts with many other proteins, including several transcription factors. Transcription factors bind to specific areas of DNA
and help control whether particular genes are turned on or off. Some of these genes likely play a role in cell growth and division.
Researchers are working to identify the proteins that interact with menin and determine its specific role as a tumor suppressor.
Health conditions
Familial isolated hyperparathyroidism
Mutations in the MEN1 gene have been found in some cases of familial isolated hyperparathyroidism, a condition characterized by
overactivity of the parathyroid glands (primary hyperparathyroidism). These glands help control the normal balance of calcium in the
blood. This balance is disrupted in familial isolated hyperparathyroidism, which can lead to high blood calcium levels
(hypercalcemia), kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue.
Primary hyperparathyroidism is the most common sign of another condition called multiple endocrine neoplasia type 1 (described
42
below); however, familial isolated hyperparathyroidism is diagnosed in people with hyperparathyroidism but not the other features of
multiple endocrine neoplasia type 1. Many of the mutations in the MEN1 gene that are associated with familial isolated
hyperparathyroidism change single protein building blocks (amino acids) in the menin protein. It is thought that these amino acid
changes impair menin's ability to interact with other proteins. Without normal menin function, cells likely divide too frequently,
leading to the formation of tumors involving the parathyroid glands. Researchers speculate that the mutations that cause familial
isolated hyperparathyroidism have a milder effect on the function of menin than the mutations that cause multiple endocrine neoplasia
type 1. Occasionally, individuals with familial isolated hyperparathyroidism later develop features of multiple endocrine neoplasia
type 1, although most never do. Familial isolated hyperparathyroidism caused by MEN1 gene mutations may be an early or mild form
of multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia
More than 1,300 mutations in the MEN1 gene have been found to cause multiple endocrine neoplasia type 1. Multiple endocrine
neoplasia typically involves the development of tumors in two or more of the body's hormone-producing glands, called endocrine
glands. These tumors can be noncancerous or cancerous. The most common endocrine glands affected in multiple endocrine neoplasia
type 1 are the parathyroid glands, the pituitary gland, and the pancreas, although additional endocrine glands and other organs can also
be involved.
Most of the MEN1 gene mutations that cause multiple endocrine neoplasia type 1 lead to the production of an abnormally short,
inactive version of menin or an unstable protein that is rapidly broken down. As a result of these mutations, one copy of the MEN1
gene in each cell makes no functional protein. If the second copy of the MEN1 gene is also altered, the cell has no working copies of
the gene and does not produce any functional menin. For unknown reasons, a second mutation occurs most often in cells of the
endocrine glands. Without menin, these cells can divide too frequently and form a tumor. Although menin appears to be necessary for
preventing tumor formation, researchers have not determined how a lack of this protein leads to the specific tumors characteristic of
multiple endocrine neoplasia type 1.
Primary macronodular adrenal hyperplasia
Primary macronodular adrenal hyperplasia (PMAH) is a disorder characterized by multiple lumps (nodules) in the adrenal glands,
which are small hormone-producing glands located on top of each kidney. These nodules, which usually are found in both adrenal
glands (bilateral) and vary in size, cause adrenal gland enlargement (hyperplasia) and result in the production of higher-than-normal
levels of the hormone cortisol. Cortisol is an important hormone that suppresses inflammation and protects the body from physical
stress such as infection or trauma through several mechanisms including raising blood sugar levels.
Other tumors
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called
somatic mutations, are not inherited. Somatic mutations in the MEN1 gene have been identified in several types of nonhereditary
(sporadic) tumors. Specifically, MEN1 gene mutations have been found in a significant percentage of noncancerous tumors of the
parathyroid glands (parathyroid adenomas); pancreatic tumors called nonfunctioning neuroendocrine tumors, gastrinomas, and
insulinomas; and cancerous tumors of the major airways in the lungs (bronchi) called bronchial carcinoids. Many of these tumor types
are also found in people who have multiple endocrine neoplasia type 1 (described above). As in multiple endocrine neoplasia, tumors
occur only when both copies of the MEN1 gene are inactivated in certain cells.
Health condition keywords
Familial isolated hyperparathyroidism
Multiple endocrine neoplasia
Primary macronodular adrenal hyperplasia
Gene: MET (MET proto-oncogene, receptor tyrosine kinase)
Normal function
This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The
encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the
mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce
lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in
cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell
carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also
associated with multiple human cancers. [provided by RefSeq, May 2016]1
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth
factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand
43
binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream
signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or
the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including
the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while
PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development
and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well
as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. Acts as a receptor
for Listeria internalin inlB, mediating entry of the pathogen into cells. A common allele in the promoter region of the MET shows
genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and
altered binding of specific transcription factor complexes. 2
Health conditions
Hepatocellular carcinoma
A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection,
chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes.
[MIM:114550] 2
Nonsyndromic hearing loss
Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. In contrast,
syndromic hearing loss occurs with signs and symptoms affecting other parts of the body. Nonsyndromic hearing loss can be classified
in several different ways. One common way is by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal
recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). Each of these types of hearing
loss includes multiple subtypes. DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. For
example, DFNA1 was the first type of autosomal dominant nonsyndromic hearing loss to be identified. Depending on the type,
nonsyndromic hearing loss can become apparent at any time from infancy to old age. Hearing loss that is present before a child learns
to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.
Renal cell carcinoma, papillary, 1
A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like
projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells
of the proximal renal tubular epithelium. [MIM:605074] 2
Other disorders
MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of
unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer
progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance
before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.
Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. 2
Health condition keyword
Hepatocellular carcinoma
Nonsyndromic hearing loss
Renal cell carcinoma, papillary, 1
Gene: MLH1 (mutL homolog 1)
Normal function
The MLH1 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes
that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein
called PMS2 (produced from the PMS2 gene), to form a protein complex. This complex coordinates the activities of other proteins
that repair mistakes made during DNA replication. The repairs are made by removing a section of DNA that contains mistakes and
replacing the section with a corrected DNA sequence. The MLH1 gene is a member of a set of genes known as the mismatch repair
(MMR) genes.
Health conditions
Lynch syndrome
44
About 50 percent of all cases of Lynch syndrome with an identified gene mutation are associated with inherited mutations in the
MLH1 gene. Several hundred MLH1 gene mutations have been found in people with this condition. Lynch syndrome increases the risk
of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal
cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries,
stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain. MLH1 gene mutations involved in this condition
prevent the production of the MLH1 protein or lead to an altered version of this protein that does not function properly. When the
MLH1 protein is absent or nonfunctional, the number of DNA mistakes that are left unrepaired during cell division increases
substantially. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally, increasing the
risk of tumor formation in the colon or another part of the body. Some mutations in the MLH1 gene cause a variant of Lynch
syndrome called Turcot syndrome. In addition to colorectal cancer, people with Turcot syndrome tend to develop a particular type of
brain tumor called a glioblastoma. Another variant of Lynch syndrome, called Muir-Torre syndrome, can also be caused by mutations
in the MLH1 gene. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon
skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily
substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, usually on sunexposed areas of skin.
Ovarian cancer
Inherited changes in the MLH1 gene increase the risk of developing ovarian cancer, as well as other types of cancer, as part of Lynch
syndrome (described above). Women with Lynch syndrome have an 8 to 10 percent chance of developing ovarian cancer in their
lifetimes, as compared with 1.6 percent in the general population.
Other cancers
While Lynch syndrome is associated with a mutation in one copy of the MLH1 gene, very rarely, individuals in affected families
inherit two MLH1 gene mutations, one from each parent. Most often in these cases, the same mutation occurs in both copies of the
gene (a homozygous mutation). People with a homozygous MLH1 gene mutation have a syndrome distinct from Lynch syndrome. In
addition to colorectal cancer, these individuals may develop cancers of the blood (leukemia or lymphoma). Some of these individuals
will also develop characteristic features of a condition known as neurofibromatosis, including noncancerous tumors that grow along
nerves (neurofibromas) and light brown patches of skin called café-au-lait spots. The onset of colon cancer in these individuals is
extremely early, often occurring during childhood. This syndrome involving colon cancer, leukemia or lymphoma, and
neurofibromatosis is sometimes called CoLoN.
Health condition keywords
Breast cancer
Café-au-lait spots
Cancers of the blood
Colorectal cancer
Lynch syndrome
Melanoma
Neurofibromatosis
Ovarian cancer
Gene MSH2 (mutS homolog 2)
Normal function
The MSH2 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes
that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other
proteins, MSH6 or MSH3 (each produced from a different gene), to form a protein complex. This complex identifies locations on the
DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then
repairs the errors. The MSH2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.
Health conditions
Lynch syndrome
About 40 percent of all cases of Lynch syndrome with an identified gene mutation are associated with inherited mutations in the
MSH2 gene. Lynch syndrome increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum,
which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the
endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain. MSH2
gene mutations involved in Lynch syndrome may cause the production of an abnormally short or inactive MSH2 protein that cannot
45
perform its normal function. When the MSH2 protein is absent or nonfunctional, the number of DNA mistakes that are left unrepaired
during cell division increases substantially. The errors accumulate as the cells continue to divide, which may cause the cells to
function abnormally, increasing the risk of tumor formation in the colon or another part of the body. Some mutations in the MSH2
gene cause a variant of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have
an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas,
which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called
keratoacanthomas may also occur, usually on sun-exposed areas of skin.
Ovarian cancer
Inherited changes in the MSH2 gene increase the risk of developing ovarian cancer, as well as other types of cancer, as part of Lynch
syndrome (described above). Women with Lynch syndrome have an 8 to 10 percent chance of developing ovarian cancer in their
lifetimes, as compared with 1.6 percent in the general population.
Heath condition keywords
Hereditary breast and ovarian cancer (HBOC)
Lynch syndrome
Ovarian cancer
Gene: MSH6 (mutS homolog 6)
Normal function
The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix
mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another
protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA
where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs
the errors. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.
Health conditions
Lynch syndrome
Mutations in the MSH6 gene have been reported in about 10 percent of families with Lynch syndrome that have an identified gene
mutation. Lynch syndrome increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum,
which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the
endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain.
Endometrial cancer is especially common in women with Lynch syndrome caused by MSH6 gene mutations. MSH6 gene mutations
involved in this condition lead to the production of an abnormally short, nonfunctional MSH6 protein or a partially active version of
the protein. When the MSH6 protein is absent or nonfunctional, the number of mistakes that are left unrepaired during cell division
increases substantially. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally,
increasing the risk of tumor formation in the colon or another part of the body. In a small number of people, mutations in the MSH6
gene cause a variant of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have
an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas,
which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called
keratoacanthomas may also occur, usually on sun-exposed areas of skin.
Ovarian cancer
Inherited changes in the MLH6 gene increase the risk of developing ovarian cancer, as well as other types of cancer, as part of Lynch
syndrome (described above). Women with Lynch syndrome have an 8 to 10 percent chance of developing ovarian cancer in their
lifetimes, as compared with 1.6 percent in the general population.
Other cancers
While Lynch syndrome is associated with a mutation in one copy of the MSH6 gene, very rarely, individuals in affected families
inherit two MSH6 gene mutations, one from each parent. Most often in these cases, the same mutation occurs in both copies of the
gene (a homozygous mutation). People with a homozygous MSH6 gene mutation have a syndrome distinct from Lynch syndrome. In
addition to colorectal cancer, they may develop cancers of the blood (leukemia or lymphoma). Some of these individuals will also
develop characteristic features of a condition known as neurofibromatosis, including noncancerous tumors that grow along nerves
(neurofibromas) and light brown patches of skin called café-au-lait spots. The onset of colon cancer in these individuals is extremely
early, often occurring during childhood. This syndrome involving colon cancer, leukemia or lymphoma, and neurofibromatosis is
sometimes called CoLoN.
46
Health condition keywords
Care-au-lait spots
Colorectal cancer
Lynch syndrome
Neurofibromatosis
Ovarian cancer
Gene: MUTYH (mutY DNA glycosylase)
Normal function
The MUTYH gene provides instructions for making an enzyme called MYH glycosylase, which is involved in the repair of DNA. This
enzyme corrects particular mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. DNA is
made up of building blocks called nucleotides, each of which has a specific partner. Normally, adenine pairs with thymine (written as
A-T) and guanine pairs with cytosine (written as G-C). During normal cellular activities, guanine sometimes becomes altered by
oxygen, which causes it to pair with adenine instead of cytosine. MYH glycosylase fixes this mistake so mutations do not accumulate
in the DNA and lead to tumor formation. This type of repair is known as base excision repair.
Health conditions
Familial adenomatous polyposis
Mutations in the MUTYH gene cause an autosomal recessive form of familial adenomatous polyposis (also called MYH-associated
polyposis). Mutations in this gene affect the ability of cells to correct mistakes made during DNA replication. In individuals who have
autosomal recessive familial adenomatous polyposis, both copies of the MUTYH gene in each cell are mutated. Most mutations in this
gene result in the production of a nonfunctional or low-functioning MYH glycosylase. When base excision repair in the cell is
impaired, mutations in other genes build up, leading to cell overgrowth and possibly tumor formation. Two mutations that change the
sequence of the building blocks of proteins (amino acids) in MYH glycosylase are common in people of European descent. One
mutation replaces the amino acid tyrosine with the amino acid cysteine at position 165 (written as Tyr165Cys or Y165C). The other
mutation switches the amino acid glycine with the amino acid aspartic acid at position 382 (written as Gly382Asp or G382D).
Health condition keyword
Familial adenomatous polyposis
Gene: NBN (nibrin)
Normal function
The NBN gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions,
including the repair of damaged DNA. Nibrin interacts with two other proteins, produced from the MRE11A and RAD50 genes, as
part of a larger protein complex. Nibrin regulates the activity of this complex by carrying the MRE11A and RAD50 proteins into the
cell's nucleus and guiding them to sites of DNA damage. The proteins work together to mend broken strands of DNA. DNA can be
damaged by agents such as toxic chemicals or radiation, and breaks in DNA strands also occur naturally when chromosomes exchange
genetic material in preparation for cell division. Repairing DNA prevents cells from accumulating genetic damage that may cause
them to die or to divide uncontrollably. The MRE11A/RAD50/NBN complex interacts with the protein produced from the ATM gene,
which plays an essential role in recognizing broken strands of DNA and coordinating their repair. The MRE11A/RAD50/NBN
complex helps maintain the stability of a cell's genetic information through its roles in repairing damaged DNA and regulating cell
division. Because these functions are critical for preventing the formation of cancerous tumors, nibrin is described as a tumor
suppressor.
Health conditions
Breast cancer
Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although
breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most
common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands
that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. A small percentage
of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations.
Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors are more likely
to develop in both breasts.
47
Nijmegen breakage syndrome
At least 10 mutations in the NBN gene have been found to cause Nijmegen breakage syndrome, a condition characterized by slow
growth, recurrent infections, and an increased risk of developing cancer. The NBN gene mutations that cause Nijmegen breakage
syndrome typically lead to the production of an abnormally short version of the nibrin protein. The mutation found in most affected
individuals, particularly in Slavic populations of Eastern Europe, deletes five DNA building blocks (nucleotides) from the NBN gene
(written as 657_661del5). This mutation leads to the production of a shortened version of the nibrin protein called p70-nibrin. This
shortened protein is not as effective as normal nibrin in responding to DNA damage, but p70-nibrin does appear to have some residual
function. When breaks in DNA are not repaired properly, genetic damage can accumulate. A buildup of mistakes in DNA can trigger
cells to grow and divide abnormally, increasing the risk of cancer in people with Nijmegen breakage syndrome. Nibrin's role in
regulating cell division and cell growth (proliferation) is thought to lead to the problems with the immune system that are seen in
affected individuals. A lack of functional nibrin results in less immune cell proliferation. A decrease in the amount of immune cells
that are produced leads to a malfunctioning immune system. It is unclear how mutations in the NBN gene cause the other features of
Nijmegen breakage syndrome.
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
Other cancers
Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several
other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in
each cell may be more likely to develop breast cancer, prostate cancer, ovarian cancer, an aggressive form of skin cancer (melanoma),
or cancer of blood-forming cells (leukemia) than people who do not carry NBN mutations. Cells with a mutation in one copy of the
NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time,
which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.
Health condition keywords
Breast cancer
Cancers of blood
Hereditary breast and ovarian cancer (HBOC)
Melanoma
Nijmegen breakage syndrome
Ovarian cancer
Prostate cancer
Gene: NF1 (neurofibromin 1)
Normal function
The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many types of cells,
including nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves. These specialized cells
form myelin sheaths, which are the fatty coverings that insulate and protect certain nerve cells. Neurofibromin acts as a tumor
suppressor protein. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. This
protein appears to prevent cell overgrowth by turning off another protein (called ras) that stimulates cell growth and division. Other
potential functions for neurofibromin are under investigation.
48
Health conditions
Neurofibromatosis type 1
More than 1,000 NF1 mutations that cause neurofibromatosis type 1 have been identified. Most of these mutations are unique to a
particular family. Many NF1 mutations result in the production of an extremely short version of neurofibromin. This shortened protein
cannot perform its normal job of inhibiting cell division. When mutations occur in both copies of the NF1 gene in Schwann cells, the
resulting loss of neurofibromin allows noncancerous tumors called neurofibromas to form. Research indicates that the formation of
neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in
wound healing and tissue repair.
Other cancers
In rare cases, inactivation of one copy of the NF1 gene in each cell increases the risk of developing juvenile myelomonocytic leukemia
(JMML). Juvenile myelomonocytic leukemia is cancer of blood-forming tissue that usually occurs in children younger than 2. This
condition causes the bone marrow to make an excessive number of immature white blood cells that cannot carry out their normal
infection-fighting functions. These abnormal cells can build up in the blood and bone marrow, leaving less room for healthy white
blood cells, red blood cells, and platelets. Children affected by this disorder may experience fatigue, fever, and easy bleeding or
bruising.
Health condition keywords
Juvenile myelomonocytic leukemia
Neurofibromatosis
Gene: NF2 (neurofibromin 2 (merlin))
Normal condition
The NF2 gene provides instructions for the production of a protein called merlin, also known as schwannomin. This protein is made in
the nervous system, particularly in specialized cells that wrap around and insulate nerves (Schwann cells). Merlin is believed to play a
role in controlling cell shape, cell movement, and communication between cells. To carry out these tasks, merlin associates with the
internal framework that supports the cell (the cytoskeleton). Merlin also functions as a tumor suppressor protein, which prevents cells
from growing and dividing too fast or in an uncontrolled way.
Health conditions
Neurofibromatosis type 2
More than 200 mutations in the NF2 gene have been identified in people with neurofibromatosis type 2. These mutations are often
inherited from an affected parent and occur in all of the body's cells. About 90 percent of NF2 mutations result in an abnormally
shortened version of the merlin protein. This short protein cannot perform its normal tumor suppressor function in cells. Research
suggests that the loss of merlin allows cells, especially Schwann cells, to multiply too frequently and form noncancerous tumors. The
most common tumors in neurofibromatosis type 2 are vestibular schwannomas, which develop along the nerve that carries information
from the inner ear to the brain. Other tumors affecting the nervous system also occur in people with this condition.
Tumors
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are known as
somatic mutations, are not inherited. Somatic mutations in the NF2 gene are involved in the development of several types of tumors,
both noncancerous (benign) and cancerous (malignant).
Somatic mutations in the NF2 gene have been associated with a disorder called schwannomatosis that is similar to neurofibromatosis
type 2. This condition is characterized by the development of multiple noncancerous tumors called schwannomas. These tumors may
develop in nerves throughout the body; however, people with schwannomatosis do not develop the vestibular schwannomas
characteristic of neurofibromatosis type 2. Although NF2 mutations are commonly found in tumors in people with schwannomatosis,
researchers do not believe that these mutations cause the disorder. Scientists are working to identify other genetic changes that are
responsible for the development of these tumors. Loss or inactivation of the NF2 gene is also associated with a common type of brain
or spinal cord tumor called a meningioma. These tumors form in the meninges, which are the thin layers of tissue that cover and
protect the brain and spinal cord. Most meningiomas are benign; only a very small percentage of meningiomas become malignant.
Mesotheliomas are cancerous tumors that can arise in the lining of the lung and chest cavity (pleura) or the lining of the abdomen
(peritoneum). These aggressive tumors are often associated with long-term exposure to asbestos. Researchers have determined that
loss or inactivation of the NF2 gene occurs in approximately half of all cases of mesothelioma.
Health condition keywords
49
Neurofibromatosis
Tumors
Gene: NSD1 (nuclear receptor binding SET domain protein 1)
Normal function
The NSD1 gene provides instructions for making a protein that functions as a histone methyltransferase. Histone methyltransferases
are enzymes that modify structural proteins called histones, which attach (bind) to DNA and give chromosomes their shape. By adding
a molecule called a methyl group to histones (a process called methylation), histone methyltransferases control (regulate) the activity
of certain genes and can turn them on and off as needed. The NSD1 enzyme controls the activity of genes involved in normal growth
and development, although most of these genes have not been identified.
Health conditions
Sotos syndrome
More than 380 mutations in the NSD1 gene have been identified in people with Sotos syndrome. The most common mutation in the
Japanese population deletes genetic material from the region of chromosome 5 that contains the NSD1 gene. In most other
populations, mutations within the gene itself are more frequent. These mutations include insertions or deletions of a small amount of
DNA and changes in single DNA building blocks (base pairs) that make up the gene. Most mutations prevent one copy of the NSD1
gene from making any enzyme or lead to the production of an abnormally small, nonfunctional version of the enzyme. Research
suggests that a reduced amount of the NSD1 enzyme disrupts the normal activity of genes involved in growth and development.
However, it remains unclear exactly how a shortage of this enzyme during development leads to overgrowth, learning disabilities, and
the other signs and symptoms of Sotos syndrome.
Other cancers
A change involving the NSD1 gene is associated with a blood cancer called childhood acute myeloid leukemia. This change occurs
when part of chromosome 5 breaks off and reattaches to part of chromosome 11. This change is acquired during a person's lifetime
and is present only in cancer cells. This type of genetic change, called a somatic mutation, is not inherited. The rearrangement of
genetic material involved in childhood acute myeloid leukemia, known as a translocation, abnormally fuses the NSD1 gene on
chromosome 5 with the NUP98 gene on chromosome 11. Research shows that the fused NUP98-NSD1 gene turns on genes that
promote the growth of immature blood cells and blocks processes that would turn the genes off. The resulting overgrowth of these
immature cells leads to development of acute myeloid leukemia. A different type of alteration involving the NSD1 gene is associated
with a cancer of nerve tissue called neuroblastoma and a type of brain cancer called glioma. This alteration, known as promoter
hypermethylation, turns off the production of the NSD1 enzyme. Researchers speculate that without NSD1, the activity of one or more
genes involved in cell growth and division is uncontrolled. As a result, the cells can grow and divide unchecked, leading to the
development of cancer.
Health condition keywords
Sotos syndrome
Gene: PALB2 (partner and localizer of BRCA2)
Normal function
This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2
early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.
[provided by RefSeq, Jul 2008]1
Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA). Functionally cooperates with
RAD51AP1 in promoting of D-loop formation by RAD51. Serves as the molecular scaffold in the formation of the BRCA1-PALB2BRCA2 complex which is essential for homologous recombination. Via its WD repeats is proposed to scaffold a HR complex
containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair. Essential partner of BRCA2 that
promotes the localization and stability of BRCA2. Also enables its recombinational repair and checkpoint functions of BRCA2. May
act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated
degradation. Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA
structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together
with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity.2
50
Health conditions
Breast cancer
A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern.
Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important
genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be
involved in different families or even in the same case. [MIM:114480] 2
Fanconi anemia
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical
abnormalities, organ defects, and an increased risk of certain cancers. More than half of people with Fanconi anemia have physical
abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or
café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi
anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and
other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped
eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the
reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile).
Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased
fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly). Individuals with Fanconi anemia have
an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors
of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with
Fanconi anemia is between 10 and 30 percent.
Fanconi anemia complementation group N
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. [MIM:610832] 2
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Pancreatic cancer 3
A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of
them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
[MIM:613348] 2
Tracheoesophageal fistula
Health condition keywords
Breast cancer
Fanconi anemia
Fanconi anemia complementation group N
Hereditary breast and ovarian cancer (HBOC)
Ovarian cancer
Pancreatic cancer 3
Gene: PHOX2B (paired like homeobox 2b)
Normal function
The PHOX2B gene provides instructions for making a protein that acts early in development to help promote the formation of nerve
cells (neurons) and regulate the process by which the neurons mature to carry out specific functions (differentiation). The protein is
51
active in the neural crest, which is a group of cells in the early embryo that give rise to many tissues and organs. Neural crest cells
migrate to form parts of the autonomic nervous system, which controls body functions such as breathing, blood pressure, heart rate,
and digestion. Neural crest cells also give rise to many tissues in the face and skull, and other tissue and cell types.
The protein produced from the PHOX2B gene contains two areas where a protein building block (amino acid) called alanine is
repeated multiple times. These stretches of alanines are known as polyalanine tracts or poly(A) tracts.
Health conditions
Congenital central hypoventilation syndrome
Most PHOX2B gene mutations that cause congenital central hypoventilation syndrome (CCHS) add extra alanines to the polyalanine
tracts in the PHOX2B protein. This type of mutation is called a polyalanine repeat expansion. Other types of PHOX2B gene mutations
have been identified in 8 to 10 percent of individuals with this disorder.
Mutations are believed to interfere with the PHOX2B protein's role in promoting neuron formation and differentiation, especially in
the autonomic nervous system, resulting in the problems regulating breathing and other autonomic nervous system dysfunction seen in
CCHS.
Neuroblastoma
Several mutations in the PHOX2B gene have been identified in people with neuroblastoma, a type of cancerous tumor composed of
immature nerve cells (neuroblasts). Neuroblastoma and other cancers occur when a buildup of genetic mutations in critical genes—
those that control cell proliferation or differentiation—allow cells to grow and divide uncontrollably to form a tumor. In most cases,
these genetic changes are acquired during a person's lifetime, called somatic mutations. Somatic mutations are present only in certain
cells and are not inherited. Less commonly, gene mutations that increase the risk of developing cancer can be inherited from a parent.
Both types of mutation occur in neuroblastoma. Somatic mutations in the PHOX2B gene increase the risk of developing sporadic
neuroblastoma, and inherited mutations in the PHOX2B gene increase the risk of developing familial neuroblastoma.
In some people with neuroblastoma, mutations in the PHOX2B gene change a single protein building block (amino acid) in the
PHOX2B protein. Other affected individuals may have an addition or deletion of several DNA building blocks (nucleotides) in the
PHOX2B gene. Addition or deletion of nucleotides changes the sequence of amino acids in the PHOX2B protein. All of these types of
mutations have been found in familial and sporadic neuroblastoma. The mutations are believed to interfere with the PHOX2B protein's
role in promoting nerve cell differentiation, which results in an excess of immature nerve cells and leads to neuroblastoma.
Other disorders
Variations in the PHOX2B gene have been associated with increased risk of certain other disorders involving the autonomic nervous
system and tissues derived from the neural crest. Particular PHOX2B gene variations have been identified in people who have both
congenital central hypoventilation syndrome and a dysfunction of the nerves in the intestine called Hirschsprung disease (this
combination of disorders is often called Haddad syndrome). The nerve problems in Hirschsprung disease result in severe constipation,
intestinal blockage, and enlargement of the colon in affected individuals. PHOX2B gene mutations have also been identified in people
with both neuroblastoma and Hirschsprung disease. In addition, PHOX2B gene variations have been identified in some babies who
died of sudden infant death syndrome (SIDS). PHOX2B gene variations likely affect the regulation of neuron differentiation in early
development, resulting in an increased risk of these disorders.
Health condition keywords
Congenital central hypoventilation syndrome
Hirschsprung disease
Neuroblastoma
Gene: PMS1 (PMS1 homolog 1, mismatch repair system component)
Normal function
This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the
repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene
cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes
involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]1
Health conditions
Lynch syndrome
Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of
many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal
52
cancer. People with Lynch syndrome also have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts,
upper urinary tract, brain, and skin. Additionally, women with this disorder have a high risk of cancer of the ovaries and lining of the
uterus (the endometrium). People with Lynch syndrome may occasionally have noncancerous (benign) growths (polyps) in the colon,
called colon polyps. In individuals with this disorder, colon polyps occur earlier but not in greater numbers than they do in the general
population.
Health condition keywords
Lynch syndrome
Gene: PMS2 (PMS1 homolog 2, mismatch repair system component)
Normal function
The PMS2 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix
mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The PMS2 protein joins with another
protein called MLH1 (produced from the MLH1 gene) to form a protein complex. This complex coordinates the activities of other
proteins that repair mistakes made during DNA replication. Repairs are made by removing the section of DNA that contains mistakes
and replacing it with a corrected DNA sequence. The PMS2 gene is a member of a set of genes known as the mismatch repair (MMR)
genes.
Health conditions
Lynch syndrome
Mutations in the PMS2 gene have been reported in about 2 percent of families with Lynch syndrome that have an identified gene
mutation. Lynch syndrome increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum,
which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the
endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain. PMS2 gene
mutations involved in this condition lead to the production of an abnormally short or inactive PMS2 protein that cannot efficiently
repair mistakes made during DNA replication. The errors accumulate as the cells continue to divide, which may cause the cells to
function abnormally, increasing the risk of tumor formation in the colon or another part of the body. Some mutations in the PMS2
gene can cause a variant of Lynch syndrome called Turcot syndrome. In addition to colorectal cancer, people with Turcot syndrome
tend to develop a particular type of brain tumor called a glioblastoma.
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Other cancers
While Lynch syndrome is associated with a mutation in one copy of the PMS2 gene, very rarely, individuals in affected families
inherit two PMS2 gene mutations, one from each parent. Most often in these cases, the same mutation occurs in both copies of the
gene (a homozygous mutation). People with a homozygous PMS2 gene mutation have a syndrome distinct from Lynch syndrome. In
addition to colorectal cancer, these individuals may develop cancers of the blood (leukemia or lymphoma). Some of these individuals
will also develop characteristic features of a condition known as neurofibromatosis, including noncancerous tumors that grow along
nerves (neurofibromas) and light brown patches of skin called café-au-lait spots. The onset of colon cancer in these individuals is
extremely early, often occurring during childhood. This syndrome involving colon cancer, leukemia or lymphoma, and
neurofibromatosis is sometimes called CoLoN.
Health condition keywords
Café-au-lait spots
Cancers of blood
Colorectal cancer
Hereditary breast and ovarian cancer (HBOC)
Lynch syndrome
Neurofibromatosis
53
Ovarian cancer
Gene: PRF1 (perforin 1)
Normal function
The PRF1 gene provides instructions for making a protein called perforin. This protein is found in immune cells (lymphocytes) called
T cells and natural killer (NK) cells, which destroy other cells. Perforin is involved in the process of cell destruction (cytolysis) and
the regulation of the immune system. Perforin is a major component of structures called cytolytic granules within T cells and NK
cells. One of the main ways in which T cells and NK cells destroy other cells is to transport and secrete these cytolytic granules, which
contain cell-killing proteins, onto the membranes of the target cells. Perforin helps create a channel through the membrane, allowing
cytolytic proteins to enter the cell and trigger it to self-destruct. This cytolytic mechanism also helps regulate the immune system by
destroying unneeded T cells. Controlling the number of T cells prevents the overproduction of immune proteins called cytokines that
lead to inflammation and which, in excess, cause tissue damage.
Health conditions
Familial hemophagocytic lymphohistiocytosis
More than 90 PRF1 gene mutations have been identified in people with familial hemophagocytic lymphohistiocytosis. These
mutations result in the production of a defective perforin protein or prevent the production of perforin. The resulting shortage of
functional perforin prevents it from carrying out its role in cell destruction and immune system regulation, leading to the exaggerated
immune response characteristic of familial hemophagocytic lymphohistiocytosis.
Other cancers
People with PRF1 gene mutations are at increased risk of developing cancers of blood-forming cells (leukemia and lymphoma). Some
of these individuals also have familial hemophagocytic lymphohistiocytosis. PRF1 gene mutations impair the immune system's ability
to destroy abnormal cells, allowing them to grow and divide in an uncontrolled way and leading to the development of cancer.
Health condition keywords
Familial hemophagocytic lymphohistiocytosis
Gene: PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha)
Normal function
The PRKAR1A gene provides instructions for making one part (subunit) of an enzyme called protein kinase A. This enzyme promotes
cell growth and division (proliferation). Protein kinase A is made up of four protein subunits, two of which are called regulatory
subunits because they control whether this enzyme is turned on or off. The PRKAR1A gene provides instructions for making one of
these regulatory subunits, called type 1 alpha. Protein kinase A remains turned off when the regulatory subunits are attached to the
other two subunits of the enzyme. In order to turn on protein kinase A, the regulatory subunits must break away from the enzyme.
Health conditions
Carney complex
More than 117 mutations in the PRKAR1A gene have been found to cause Carney complex. Most of these mutations result in an
abnormal type 1 alpha regulatory subunit that is quickly broken down (degraded) by the cell. The lack of this regulatory subunit
causes protein kinase A to be turned on more often than normal, which leads to uncontrolled cell proliferation. The signs and
symptoms of Carney complex are related to the unregulated growth of cells in many parts of the body.
Health condition keywords
Carney complex
Gene: PTCH1 (patched 1)
Normal function
The PTCH1 gene provides instructions for producing the patched-1 protein, which functions as a receptor. Receptor proteins have
specific sites into which certain other proteins, called ligands, fit like keys into locks. A protein called Sonic Hedgehog is the ligand
for the patched-1 receptor. Together, ligands and their receptors trigger signals that affect cell development and function. Patched-1
and Sonic Hedgehog function in a pathway that is essential for early development. This pathway plays a role in cell growth, cell
specialization, and determining the shape (patterning) of many different parts of the developing body. When Sonic Hedgehog is not
54
present, patched-1 prevents cells from growing and dividing (proliferating). When Sonic Hedgehog is attached, patched-1 stops
suppressing cell proliferation. Based on its role in preventing cells from proliferating in an uncontrolled way, PTCH1 is called a tumor
suppressor gene.
Health conditions
9q22.3 microdeletion
The PTCH1 gene is located in a region of chromosome 9 that is deleted in people with a 9q22.3 microdeletion. As a result of this
deletion, affected individuals are missing one copy of the PTCH1 gene in each cell. Researchers believe that many of the features
associated with 9q22.3 microdeletions, particularly the signs and symptoms of Gorlin syndrome (described above), result from a loss
of the PTCH1 gene. When this gene is missing, patched-1 is not available to suppress cell proliferation. As a result, cells divide
uncontrollably to form the tumors that are characteristic of Gorlin syndrome. Other signs and symptoms related to 9q22.3
microdeletions (such as delayed development, intellectual disability, overgrowth of the body, and other physical abnormalities) may
result from the loss of additional genes in the deleted region of chromosome 9.
Gorlin syndrome
More than 225 mutations in the PTCH1 gene have been found to cause Gorlin syndrome (also known as nevoid basal cell carcinoma
syndrome), a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous
tumors. Mutations in this gene prevent the production of patched-1 or lead to the production of an abnormal version of the receptor.
An altered or missing patched-1 receptor cannot effectively suppress cell growth and division. As a result, cells proliferate
uncontrollably to form the tumors that are characteristic of Gorlin syndrome. It is less clear how PTCH1 gene mutations cause the
other signs and symptoms related to this condition, including small depressions (pits) in the skin of the palms of the hands and soles of
the feet, an unusually large head size (macrocephaly), and skeletal abnormalities.
Nonsyndromic holoprosencephaly
Nonsyndromic holoprosencephaly is an abnormality of brain development that also affects the head and face. Normally, the brain
divides into two halves (hemispheres) during early development. Holoprosencephaly occurs when the brain fails to divide properly
into the right and left hemispheres. This condition is called nonsyndromic to distinguish it from other types of holoprosencephaly
caused by genetic syndromes, chromosome abnormalities, or substances that cause birth defects (teratogens). The severity of
nonsyndromic holoprosencephaly varies widely among affected individuals, even within the same family. People with nonsyndromic
holoprosencephaly often have a small head (microcephaly), although they can develop a buildup of fluid in the brain (hydrocephalus)
that causes increased head size (macrocephaly). Other features may include an opening in the roof of the mouth (cleft palate) with or
without a split in the upper lip (cleft lip), one central front tooth instead of two (a single maxillary central incisor), and a flat nasal
bridge. The eyeballs may be abnormally small (microphthalmia) or absent (anophthalmia).
Other cancers
Some mutations are acquired during a person's lifetime and are present only in certain cells. These genetic changes, called somatic
mutations, are not inherited. Somatic mutations in both copies of the PTCH1 gene are associated with a non-hereditary (sporadic) type
of skin cancer called basal cell carcinoma. Other sporadic types of cancer may be associated with somatic mutations in the PTCH1
gene, including some forms of skin cancer, a childhood brain tumor called medulloblastoma, breast cancer, and colon cancer. A
noncancerous (benign) jaw tumor called a keratocystic odontogenic tumor can also be associated with somatic PTCH1 gene
mutations.
Other disorders
At least seven mutations in the PTCH1 gene have been found to cause nonsyndromic holoprosencephaly. This condition occurs when
the brain fails to divide into two halves during early development. PTCH1 gene mutations are a rare cause of nonsyndromic
holoprosencephaly. These mutations prevent the signaling that is necessary for normal brain cell patterning. The signs and symptoms
of nonsyndromic holoprosencephaly are caused by abnormal development of the brain and face.
Health condition keywords
9q22.3 microdeletion
Gorlin syndrome
Nonsyndromic holoprosencephaly
55
Gene: PTEN (phosphatase and tensin homolog)
Normal function
The PTEN gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor
suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing too rapidly or in an
uncontrolled way. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists
of three oxygen atoms and one phosphorus atom. Enzymes with this function are called phosphatases. The PTEN enzyme is part of a
chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence
suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the
formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic
information. All of these functions help prevent uncontrolled cell growth that can lead to the formation of tumors.
Health conditions
Bannayan-Riley-Ruvalcaba syndrome
More than 30 mutations in the PTEN gene have been found to cause Bannayan-Riley-Ruvalcaba syndrome. Common features of this
condition include a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and
dark freckles on the penis in males. Bannayan-Riley-Ruvalcaba syndrome is one of several related conditions that are often considered
together as PTEN hamartoma tumor syndrome. Some of the mutations that cause Bannayan-Riley-Ruvalcaba syndrome change single
DNA building blocks (base pairs) in the PTEN gene or insert or delete a small number of base pairs. Other mutations result in an
abnormally short enzyme or reduce the amount of enzyme that is produced. In about 10 percent of cases, Bannayan-Riley-Ruvalcaba
syndrome results from the deletion of a large amount of genetic material that includes part or the entire PTEN gene. All of these
genetic changes prevent the PTEN enzyme from regulating cell proliferation effectively, which can lead to uncontrolled cell growth
and the formation of hamartomas and other types of tumors. It is unclear how PTEN gene mutations cause macrocephaly and the other
features of Bannayan-Riley-Ruvalcaba syndrome.
Breast cancer
Inherited mutations in the PTEN gene increase the risk of developing breast cancer. In many cases, this increased risk occurs as part of
Cowden syndrome (described above). Inherited mutations in the PTEN gene are thought to account for only a small fraction of all
breast cancer cases. Noninherited (somatic) PTEN gene mutations occur in some breast cancers in women without a family history of
the disease. Somatic mutations are not inherited and do not occur as part of a familial cancer syndrome. They are acquired during a
person's lifetime and occur only in certain cells in the breast. These mutations impair the tumor suppressor function of the PTEN
enzyme, allowing cells to grow and divide without control or order. This uncontrolled cell growth contributes to the formation of a
cancerous tumor. Studies suggest that a loss of functional PTEN enzyme is also related to poor responsiveness to a drug called
trastuzumab (Herceptin), which is used to treat breast cancer.
Cowden syndrome
Researchers have identified more than 300 mutations in the PTEN gene that can cause Cowden syndrome or a similar disorder called
Cowden-like syndrome. These conditions are characterized by the growth of multiple hamartomas and an increased risk of developing
certain cancers, particularly breast cancer, thyroid cancer, and cancer of the uterine lining (endometrial cancer). Cowden syndrome
and Cowden-like syndrome are considered to be part of PTEN hamartoma tumor syndrome (described below). Mutations that cause
Cowden syndrome and Cowden-like syndrome include changes in a small number of base pairs and, in some cases, deletions of a
larger amount of genetic material from the PTEN gene. These mutations lead to the production of a PTEN enzyme that does not
function properly or does not work at all. The altered enzyme is unable to restrain cell division or signal abnormal cells to die, which
contributes to the development of hamartomas and cancerous tumors.
Head and neck squamous cell carcinoma
Squamous cell carcinoma is a cancer that arises from particular cells called squamous cells. Squamous cells are found in the outer
layer of skin and in the mucous membranes, which are the moist tissues that line body cavities such as the airways and intestines.
Head and neck squamous cell carcinoma (HNSCC) develops in the mucous membranes of the mouth, nose, and throat. HNSCC is
classified by its location: it can occur in the mouth (oral cavity), the middle part of the throat near the mouth (oropharynx), the space
behind the nose (nasal cavity and paranasal sinuses), the upper part of the throat near the nasal cavity (nasopharynx), the voicebox
(larynx), or the lower part of the throat near the larynx (hypopharynx). Depending on the location, the cancer can cause abnormal
patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore
throat, earache, pain when swallowing or difficulty swallowing, a hoarse voice, difficulty breathing, or enlarged lymph nodes.
HNSCC can spread (metastasize) to other parts of the body, such as the lymph nodes or lungs. If it spreads, the cancer has a worse
prognosis and can be fatal. About half of affected individuals survive more than five years after diagnosis.
56
Lung cancer
Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung
cancer may or may not cause signs or symptoms in its early stages. Some people with lung cancer have chest pain, frequent coughing,
breathing problems, trouble swallowing or speaking, blood in the mucus, loss of appetite and weight loss, fatigue, or swelling in the
face or neck. Lung cancer occurs most often in adults in their sixties or seventies. Most people who develop lung cancer have a history
of long-term tobacco smoking; however, the condition can occur in people who have never smoked. Lung cancer is generally divided
into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a
microscope. Non-small cell lung cancer accounts for 85 percent of lung cancer, while small cell lung cancer accounts for the
remaining 15 percent.
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
Other cancers
Somatic mutations in the PTEN gene are among the most common genetic changes found in human cancers. The cancers associated
with somatic mutations are not inherited and do not occur as part of a cancer syndrome. Somatic mutations in the PTEN gene have
been reported in many types of cancer, and studies suggest that PTEN may be the most frequently mutated gene in prostate cancer and
endometrial cancer. PTEN gene mutations are also commonly found in brain tumors called glioblastomas and astrocytomas, and in an
aggressive form of skin cancer called melanoma. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the
PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of
cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.
Other disorders
Several related conditions caused by mutations in the PTEN gene, including Bannayan-Riley-Ruvalcaba syndrome and Cowden
syndrome, are often considered together as PTEN hamartoma tumor syndrome. The mutations that cause these conditions are present
in cells throughout the body and are often inherited from a parent. Some of the mutations that cause PTEN hamartoma tumor
syndrome lead to a defective version of the PTEN enzyme that cannot perform its function as a tumor suppressor. Other mutations
prevent the PTEN gene from producing any enzyme at all. Without functional PTEN enzyme, cell division is not controlled effectively
and damaged cells continue to divide inappropriately, leading to the development of hamartomas and other tumors. In some published
case reports, mutations in the PTEN gene have been associated with Proteus syndrome, a rare condition characterized by asymmetric
overgrowth of the bones, skin, and other tissues. However, many researchers now believe that individuals with PTEN gene mutations
and asymmetric overgrowth do not meet the strict guidelines for a diagnosis of Proteus syndrome. Instead, these individuals have a
condition that is considered part of PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is
segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2
segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome. PTEN gene mutations
have been identified in several people who have both macrocephaly and the characteristic features of autism, a developmental disorder
that affects communication and social interaction. Many of these mutations change single protein building blocks (amino acids) in the
PTEN enzyme or lead to the production of an abnormally short version of the enzyme. It is unknown how changes in the PTEN gene
are related to the risk of developing autism. Some of these mutations have also been reported in families with PTEN hamartoma tumor
syndrome, and it is unclear how these mutations can cause different disorders
Health condition keywords
Bannayan-Riley-Ruvalcaba syndrome
Breast cancer
Colorectal cancer
Cowden syndrome
Head and neck squamous cell carcinoma
Hereditary breast and ovarian cancer (HBOC)
Lung cancer
Melanoma
Prostate cancer
57
Gene: RAD51C (RAD51 paralog C)
Normal function
This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces
cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with
other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with
Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs
frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in
tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]1
Essential for the homologous recombination (HR) pathway of DNA repair. Involved in the homologous recombination repair (HRR)
pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Part of the RAD21
paralog protein complexes BCDX2 and CX3 which act at different stages of the BRCA1-BRCA2-dependent HR pathway. Upon DNA
damage, BCDX2 seems to act downstream of BRCA2 recruitment and upstream of RAD51 recruitment; CX3 seems to act
downstream of RAD51 recruitment; both complexes bind predominantly to the intersection of the four duplex arms of the Holliday
junction (HJ) and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, singlestranded gaps in duplex DNA and specifically to nicks in duplex DNA. The BCDX2 subcomplex RAD51B:RAD51C exhibits singlestranded DNA-dependent ATPase activity suggesting an involvement in early stages of the HR pathway. Involved in RAD51 foci
formation in response to DNA damage suggesting an involvement in early stages of HR probably in the invasion step. Has an early
function in DNA repair in facilitating phosphorylation of the checkpoint kinase CHEK2 and thereby transduction of the damage
signal, leading to cell cycle arrest and HR activation. Participates in branch migration and HJ resolution and thus is important for
processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex. Part of a PALB2scaffolded HR complex containing BRCA2 and which is thought to play a role in DNA repair by HR. Protects RAD51 from ubiquitinmediated degradation that is enhanced following DNA damage. Plays a role in regulating mitochondrial DNA copy number under
conditions of oxidative stress in the presence of RAD51 and XRCC3. Contributes to DNA cross-link resistance, sister chromatid
cohesion and genomic stability. Involved in maintaining centrosome number in mitosis.2
Health conditions
Breast cancer
Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although
breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most
common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands
that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. A small percentage
of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations.
Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors are more likely
to develop in both breasts.
Breast-ovarian cancer, familial 3
A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are
an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts,
or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific
organs, such as the prostate. [MIM:613399] 2
Fanconi anemia
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical
abnormalities, organ defects, and an increased risk of certain cancers. More than half of people with Fanconi anemia have physical
abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or
café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi
anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and
other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped
eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the
reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile).
Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased
fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly). Individuals with Fanconi anemia have
an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors
of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with
Fanconi anemia is between 10 and 30 percent.
58
Fanconi anemia, complementation group O
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. [MIM:613390] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Breast cancer
Fanconi anemia
Fanconi anemia, complementation group O
Hereditary breast and ovarian cancer (HBOC)
Ovarian cancer
Tracheoesophageal fistula
Gene: RAD51D (RAD51 paralog D)
Normal function
The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial
RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA.
This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The
protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA,
and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript
variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1
(RFFL) gene. [provided by RefSeq, Jan 2011]1
Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or
induced by DNA-damaging agents. Bind to single-stranded DNA (ssDNA) and has DNA-dependent ATPase activity. Part of the
Rad21 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts
downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four
duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind singlestranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. Involved in telomere maintenance. The
BCDX2 subcomplex XRCC2:RAD51D can stimulate Holliday junction resolution by BLM.2
Health conditions
Breast-ovarian cancer, familial 4
A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are
an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts,
or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific
organs, such as the prostate. [MIM:614291] 2
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
59
Health condition keywords
Breast cancer
Hereditary breast and ovarian cancer (HBOC)
Ovarian cancer
Gene: RB1 (RB transcriptional corepressor 1)
Normal function
The RB1 gene provides instructions for making a protein called pRB. This protein acts as a tumor suppressor, which means that it
regulates cell growth and keeps cells from dividing too fast or in an uncontrolled way. Under certain conditions, pRB stops other
proteins from triggering DNA replication, the process by which DNA makes a copy of itself. Because DNA replication must occur
before a cell can divide, tight regulation of this process controls cell division and helps prevent the growth of tumors. Additionally,
pRB interacts with other proteins to influence cell survival, the self-destruction of cells (apoptosis), and the process by which cells
mature to carry out special functions (differentiation).
Health conditions
Bladder cancer
Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called
somatic mutations, are not inherited. Somatic mutations that turn off (inactivate) the RB1 gene have been reported in some cases of
bladder cancer. Mutations in RB1 are thought to contribute to the development of bladder cancer, and these genetic changes may help
predict whether tumors will grow rapidly and spread to other tissues.
Retinoblastoma
Hundreds of mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that typically
affects young children. This cancer develops in the retina, which is the specialized light-sensitive tissue at the back of the eye that
detects light and color. Researchers estimate that 40 percent of all retinoblastomas are germinal, which means that RB1 mutations
occur in all of the body's cells and can be passed to the next generation. The other 60 percent are non-germinal, which means that RB1
mutations occur only in the eye and cannot be passed to the next generation. In germinal retinoblastoma, an RB1 mutation is present
in all of the body's cells. For retinoblastoma to develop, the other copy of the RB1 gene also must be mutated or lost. This second
mutation typically occurs early in life in retinal cells. Cells with two altered copies of the RB1 gene produce no functional pRB and
are unable to regulate cell division effectively. As a result, retinal cells lacking functional pRB can divide uncontrollably to form
cancerous tumors. Some studies suggest that additional genetic changes can influence the development of retinoblastoma; these
changes may help explain variations in the development and growth of tumors in different people. In people with germinal
retinoblastoma, RB1 mutations increase the risk of several other cancers outside the eye. Specifically, these people are more likely to
develop a cancer of the pineal gland in the brain (pinealoma), a type of bone cancer known as osteosarcoma, cancers of soft tissues
such as muscle, and an aggressive form of skin cancer called melanoma.
Non-germinal retinoblastoma occurs in people with no history of the disorder in their family. Affected individuals are born with two
normal copies of the RB1 gene. Then, usually in early childhood, both copies of the gene in retinal cells acquire mutations or are lost.
These genetic changes prevent the cells from producing any functional pRB. The loss of this protein allows retinal cells to grow and
divide without control or order, leading to the development of a cancerous tumor.
Other cancers
In addition to bladder cancer, somatic mutations in the RB1 gene are associated with many other types of cancer. For example,
changes in the RB1 gene have been reported in some cases of lung cancer, breast cancer, a bone cancer known as osteosarcoma, and
an aggressive form of skin cancer called melanoma. Somatic RB1 mutations have also been identified in some leukemias, which are
cancers of blood-forming cells. Somatic RB1 mutations in cancer cells inactivate pRB so it can no longer regulate cell division
effectively.
Health condition keywords
Bladder cancer
Retinoblastoma
Gene: RECQL4 (RecQ like helicase 4)
Normal function
The RECQL4 gene provides instructions for making one member of a protein family called RecQ helicases. Helicases are enzymes
that bind to DNA and temporarily unwind the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for
60
copying (replicating) DNA in preparation for cell division, and for repairing damaged DNA. Because RecQ helicases maintain the
structure and integrity of DNA, they are known as the "caretakers of the genome." The RECQL4 protein is active in several types of
cells before and after birth. Researchers believe that this protein is particularly important in cells of the developing bones and skin. It
has also been found in enterocytes, which are cells that line the intestine and absorb nutrients.
Health conditions
Baller-Gerold syndrome
Several mutations in the RECQL4 gene have been identified in people with Baller-Gerold syndrome. Most of these mutations prevent
the production of any RECQL4 protein or change the way the protein is pieced together, which disrupts its usual function. A shortage
of this protein may prevent normal DNA replication and repair, causing widespread damage to a person's genetic information over
time. It is unclear how these changes result in the varied signs and symptoms of Baller-Gerold syndrome, including the abnormal
fusion of certain skull bones (craniosynostosis), small stature, missing thumbs or bones in the forearm (radial ray malformations), and
a skin rash.
Rapadilino syndrome
At least 10 mutations in the RECQL4 gene have been identified in people with RAPADILINO syndrome. This condition has many
features, including radial ray malformations, malformed or missing kneecaps, diarrhea, and short stature. The condition was first
identified in Finland, and the most common mutation in RAPADILINO syndrome is found in all affected individuals of Finnish
descent as well as some people from other populations. This mutation, which is written as IVS7+2delT, is known as a splice-site
mutation, and it causes the RECQL4 protein to be pieced together incorrectly. This genetic change results in the production of a
protein that is missing a region called exon 7. The altered protein does not have helicase activity, which may prevent normal DNA
replication and repair. These changes may result in the accumulation of DNA errors and cell death, although it is unclear exactly how
RECQL4 gene mutations lead to the specific features of RAPADILINO syndrome.
Rothmund-Thomson syndrome
More than 40 mutations in the RECQL4 gene have been found in people with Rothmund-Thomson syndrome. These mutations likely
prevent the production of any RECQL4 protein or lead to the production of an abnormally short, nonfunctional version of the protein.
A shortage of this protein may prevent normal DNA replication and repair, causing widespread damage to a person's genetic
information over time. Further study is needed to determine how these changes result in the characteristic features of RothmundThomson syndrome, which include a skin rash, sparse hair, small stature, skeletal abnormalities, and an increased risk of certain
cancers. Because Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO syndrome have overlapping features
and can be caused by mutations in the same gene, researchers are investigating whether they are separate disorders or part of a single
syndrome with overlapping signs and symptoms.
Health condition keywords
Baller-Gerold syndrome
Rapadilino syndrome
Rothmund-Thomson syndrome
Gene: RET (ret proto-oncogene)
Normal function
The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be
essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons) and the portion
of the nervous system that controls involuntary body functions such as heart rate (the autonomic nervous system). The RET protein is
also necessary for normal kidney development and the production of sperm (spermatogenesis). The RET protein spans the cell
membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This
positioning of the protein allows it to interact with specific factors outside the cell and to receive signals that help the cell respond to
its environment. When molecules that stimulate growth and development (growth factors) attach to the RET protein, a complex
cascade of chemical reactions inside the cell is triggered. These reactions instruct the cell to undergo certain changes, such as dividing
or maturing to take on specialized functions.
Health conditions
61
Hirschsprung disease
Mutations in the RET gene are the most common genetic cause of Hirschsprung disease, a disorder that causes severe constipation or
blockage of the intestine. More than 200 RET gene mutations are known to cause this condition. These genetic changes result in a
nonfunctional version of the RET protein that cannot interact with growth factors or transmit signals within cells. Without RET
protein signaling, enteric nerves do not develop properly. These nerves control contractions that move stool through the intestine, and
their absence leads to the intestinal problems characteristic of Hirschsprung disease.
Multiple endocrine neoplasia
More than 25 mutations in the RET gene are known to cause a form of multiple endocrine neoplasia called type 2. Multiple endocrine
neoplasia typically involves the development of tumors in two or more of the body's hormone-producing glands, called endocrine
glands. These tumors can be noncancerous or cancerous. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A,
type 2B, and familial medullary thyroid carcinoma. These subtypes are distinguished by their characteristic signs and symptoms and
risk of specific tumors. Most of the RET gene mutations that cause multiple endocrine neoplasia type 2 change single protein building
blocks (amino acids) in the RET protein. Type 2A most often results from a mutation that substitutes the amino acid arginine for the
amino acid cysteine at position 634 (written as Cys634Arg or C634R). More than 90 percent of cases of type 2B are caused by a
mutation that replaces the amino acid methionine with the amino acid threonine at position 918 (written as Met918Thr or M918T).
Several amino acid substitutions can cause familial medullary thyroid carcinoma. The mutations responsible for multiple endocrine
neoplasia type 2 result in an overactive RET protein that can transmit signals without first attaching to growth factors outside the cell.
The overactive protein likely triggers cells to grow and divide abnormally, which can lead to the formation of tumors in the endocrine
system and other tissues. The overactivating RET gene mutations that cause multiple endocrine neoplasia type 2 are very different
from the inactivating mutations that cause Hirschsprung disease (described above); these two disorders rarely occur in the same
individual.
Nonsyndromic paraganglioma
Mutations in the RET gene increase the risk of developing a type of paraganglioma called pheochromocytoma. Paragangliomas are
tumors of the nervous system that are usually noncancerous (benign). Pheochromocytomas specifically affect the adrenal glands,
which are small hormone-producing glands located on top of each kidney. Pheochromocytomas are a feature of multiple endocrine
neoplasia type 2, but they can also be nonsyndromic, which means they occur without the other signs and symptoms of the syndrome.
RET gene mutations associated with nonsyndromic pheochromocytoma change single amino acids in the RET protein. As in multiple
endocrine neoplasia type 2, the mutations likely result in an overactive RET protein that can trigger cells to grow and divide
uncontrollably and can lead to the formation of tumors.
Health condition keywords
Hirschsprung disease
Multiple endocrine neoplasia
Nonsyndromic paraganglioma
Gene: RHBDF2 (rhomboid 5 homolog 2)
Normal function
RHBDF2 (Rhomboid 5 Homolog 2 (Drosophila)) is a Protein Coding gene. Diseases associated with RHBDF2 include tylosis with
esophageal cancer and esophageal cancer. Among its related pathways are signaling by GPCR and immune System. GO annotations
related to this gene include serine-type endopeptidase activity and growth factor binding. An important paralog of this gene is
RHBDF1. Rhomboid protease-like protein which has no protease activity but regulates the secretion of several ligands of the
epidermal growth factor receptor. Indirectly activates the epidermal growth factor receptor signaling pathway and may thereby
regulate sleep, cell survival, proliferation and migration (By similarity).
Health conditions
Tylosis with esophageal cancer
A genetic disorder characterized by thickening (hyperkeratosis) of the palms and soles, white patches in the mouth (oral leukoplakia),
and a very high risk of esophageal cancer. This is the only genetic syndrome known to predispose to squamous cell carcinoma of the
esophagus. The risk of developing esophageal cancer is 95% by age 70. The syndrome is inherited in an autosomal dominant manner.
The gene has been mapped to chromosome 17q25 but has not been identified. The syndrome is also called nonepidermolytic
palmoplantar keratoderma.
Health condition keywords
Tylosis with esophageal cancer
62
Gene: RUNX1(runt related transcription factor 1)
Normal function
The RUNX1 gene provides instructions for making a protein called runt-related transcription factor 1 (RUNX1). Like other
transcription factors, the RUNX1 protein attaches (binds) to specific regions of DNA and helps control the activity of particular genes.
This protein interacts with another protein called core binding factor beta or CBFβ (produced from the CBFB gene), which helps
RUNX1 bind to DNA and prevents it from being broken down. Together, these proteins form one version of a complex known as core
binding factor (CBF). The RUNX1 protein turns on (activates) genes that help control the development of blood cells (hematopoiesis).
In particular, it plays an important role in development of hematopoietic stem cells, early blood cells that have the potential to develop
into all types of mature blood cells such as white blood cells, red blood cells, and platelets.
Health conditions
Core binding factor acute myeloid leukemia
A rearrangement (translocation) of genetic material involving the RUNX1 gene is found in approximately 7 percent of individuals with
a form of blood cancer known as acute myeloid leukemia (AML). The translocation, written as t(8;21), combines genetic information
from chromosome 21 and chromosome 8, fusing the RUNX1 gene on chromosome 21 with a gene on chromosome 8 called RUNX1T1
(also known as ETO). Because this genetic change affects CBF, the condition is classified as core binding factor AML (CBF-AML).
The resulting fusion protein, RUNX1-ETO, is able to form CBF and attach to DNA, like the normal RUNX1 protein; however, instead
of turning genes on, it turns them off. This change in gene activity blocks the maturation (differentiation) of blood cells and leads to
the production of abnormal, immature white blood cells called myeloid blasts. While t(8;21) is important for leukemia development, a
mutation in one or more additional genes is typically needed for the myeloid blasts to develop into cancerous leukemia cells.
Cytogenetically normal acute myeloid leukemia
Cytogenetically normal acute myeloid leukemia (CN-AML) is one form of a cancer of the blood-forming tissue (bone marrow) called
acute myeloid leukemia. In normal bone marrow, early blood cells called hematopoietic stem cells develop into several types of blood
cells: white blood cells (leukocytes) that protect the body from infection, red blood cells (erythrocytes) that carry oxygen, and platelets
(thrombocytes) that are involved in blood clotting. In acute myeloid leukemia, the bone marrow makes large numbers of abnormal,
immature white blood cells called myeloid blasts. Instead of developing into normal white blood cells, the myeloid blasts develop into
cancerous leukemia cells. The large number of abnormal cells in the bone marrow interferes with the production of functional white
blood cells, red blood cells, and platelets. The age at which CN-AML begins ranges from childhood to late adulthood. CN-AML is
said to be an intermediate-risk cancer because the prognosis varies: some affected individuals respond well to normal treatment while
others may require stronger treatments. The age at which the condition begins and the prognosis are affected by the specific genetic
factors involved in the condition.
Rheumatoid arthritis
Rheumatoid arthritis is a disease that causes chronic abnormal inflammation, primarily affecting the joints. The most common signs
and symptoms are pain, swelling, and stiffness of the joints. Small joints in the hands and feet are involved most often, although larger
joints (such as the shoulders, hips, and knees) may become involved later in the disease. Joints are typically affected in a symmetrical
pattern; for example, if joints in the hand are affected, both hands tend to be involved. People with rheumatoid arthritis often report
that their joint pain and stiffness is worse when getting out of bed in the morning or after a long rest. Rheumatoid arthritis can also
cause inflammation of other tissues and organs, including the eyes, lungs, and blood vessels. Additional signs and symptoms of the
condition can include a loss of energy, a low fever, weight loss, and a shortage of red blood cells (anemia). Some affected individuals
develop rheumatoid nodules, which are firm lumps of noncancerous tissue that can grow under the skin and elsewhere in the body.
The signs and symptoms of rheumatoid arthritis usually appear in mid- to late adulthood. Many affected people have episodes of
symptoms (flares) followed by periods with no symptoms (remissions) for the rest of their lives. In severe cases, affected individuals
have continuous health problems related to the disease for many years. The abnormal inflammation can lead to severe joint damage,
which limits movement and can cause significant disability.
Other disorders
Translocations and other types of mutations involving the RUNX1 gene have been associated with different types of leukemia and
related blood disorders, including acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), familial platelet
disorder with predisposition to acute myeloid leukemia, and myelodysplastic syndromes (MDS). Depending on the type of mutation,
these conditions can be related to impaired regulation of gene activity or loss of normal gene function. The RUNX1 gene mutations
associated with these diseases are somatic mutations and are not inherited. They are found only in certain cells of the body.
Health condition keywords
63
Core binding factor acute myeloid leukemia
Cytogenetically normal acute myeloid leukemia
Rheumatoid arthritis
Gene: SBDS (SBDS ribosome assembly guanine nucleotide exchange factor)
Normal function
The SBDS gene provides instructions for making a protein whose function is unknown. Because mutations in this gene cause health
problems affecting many body systems, researchers believe that the SBDS protein has an essential function in cells throughout the
body. Studies suggest that the SBDS protein may play a role in processing RNA, a molecule that is a chemical cousin of DNA. This
protein may also be involved in building ribosomes, which are cellular structures that use the instructions encoded by RNA to create
proteins. More research is needed to clarify the protein's role in these processes.
Health conditions
Shwachman-Diamond syndrome
At least 20 mutations in the SBDS gene have been identified in people with Shwachman-Diamond syndrome. Most of these mutations
result from an exchange of genetic material between the SBDS gene and a very similar, but nonfunctional, piece of DNA called a
pseudogene, which is located very close to the SBDS gene on chromosome 7. This type of DNA exchange is called a gene conversion.
The genetic material from the pseudogene contains errors that, when introduced into the SBDS gene, disrupt the way the gene's
instructions are used to make a protein.
The two most common mutations in people with Shwachman-Diamond syndrome result from exchanges between the SBDS gene and
the nearby pseudogene. One of these mutations, written as 258+2T>C, changes a single DNA building block (nucleotide) in a region
of the gene known as intron 2. This mutation, which is called a splice-site mutation, prevents the production of any functional SBDS
protein. The other common mutation, written as 183-184TA>CT, changes two nucleotides in the SBDS gene. This genetic change
introduces a premature stop signal in the instructions for making the SBDS protein. It is unclear whether this mutation results in an
abnormally shortened protein or prevents any protein from being made. The features of Shwachman-Diamond syndrome result when
mutations impair the normal function of the SBDS protein. Because the protein's function is unknown, researchers have not
determined how these mutations underlie the bone marrow abnormalities, increased cancer risk, and other signs and symptoms of this
condition.
Health condition keywords
Shwachman-Diamond syndrome
Gene: SDHAF2 (succinate dehydrogenase complex assembly factor 2)
Normal function
The SDHAF2 gene provides instructions for making a protein that interacts with the succinate dehydrogenase (SDH) enzyme. The
SDHAF2 protein helps a molecule called FAD attach to the SDH enzyme. FAD is called a cofactor because it helps the enzyme carry
out its function. The FAD cofactor is required for SDH enzyme activity.
The SDH enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form
that cells can use. Within mitochondria, the SDH enzyme links two important pathways in energy conversion: the citric acid cycle (or
Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to
another compound called fumarate.
Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that
stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible
factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell
division and the formation of new blood vessels in a hypoxic environment. The SDHAF2 gene is a tumor suppressor, which means it
prevents cells from growing and dividing in an uncontrolled way.
Health conditions
Hereditary parapanglioma-pheochromocytoma
At least one mutation in the SDHAF2 gene has been identified in people with hereditary paraganglioma-pheochromocytoma type 2.
People with this condition have paragangliomas, pheochromocytomas, or both. These noncancerous (benign) tumors are associated
with the nervous system. The mutation replaces a protein building block (amino acid) in the SDHAF2 protein. Specifically, the amino
acid glycine is replaced with the amino acid arginine at position 78 (written as Gly78Arg or G78R). The interaction between the
mutated SDHAF2 protein and the SDH complex is impaired, and attachment of the FAD cofactor is decreased. As a result, the SDH
64
enzyme is nonfunctional. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell.
Excess succinate abnormally stabilizes HIF, which also builds up in cells. Excess HIF stimulates cells to divide and triggers the
production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood
vessels, can lead to the development of tumors in people with hereditary paraganglioma-pheochromocytoma.
Health condition keywords
Hereditary parapanglioma-pheochromocytoma
Gene: SDHB (succinate dehydrogenase complex iron sulfur subunit B)
Normal function
The SDHB gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH
enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells
can use. Within mitochondria, the SDH enzyme links two important pathways in energy conversion: the citric acid cycle (or Krebs
cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to
another compound called fumarate. Negatively charged particles called electrons are released during this reaction. The SDHB protein
provides an attachment site for electrons as they are transferred to the oxidative phosphorylation pathway. In oxidative
phosphorylation, the electrons help create an electrical charge that provides energy for the production of adenosine triphosphate
(ATP), the cell's main energy source. Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can
help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a
protein called hypoxia-inducible factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several
important genes involved in cell division and the formation of new blood vessels in a hypoxic environment. The SDHB gene is a
tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.
Health conditions
Cowden syndrome
At least 10 variants in the SDHB gene have been identified in people with Cowden syndrome or a similar disorder called Cowden-like
syndrome. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of developing
certain cancers, particularly breast cancer, thyroid cancer, and cancer of the uterine lining (endometrial cancer). The SDHB gene
variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHB protein, which likely
alters the function of the SDH enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked,
leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHB gene
variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely
been found in people without the features of these conditions.
Gastrointestinal stromal tumor
A gastrointestinal stromal tumor (GIST) is a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or
small intestine. The tumors are thought to grow from specialized cells found in the gastrointestinal tract called interstitial cells of Cajal
(ICCs) or precursors to these cells. GISTs are usually found in adults between ages 40 and 70; rarely, children and young adults
develop these tumors. The tumors can be cancerous (malignant) or noncancerous (benign). Affected individuals with no family history
of GIST typically have only one tumor (called a sporadic GIST). People with a family history of GISTs (called familial GISTs) often
have multiple tumors and additional signs or symptoms, including noncancerous overgrowth (hyperplasia) of other cells in the
gastrointestinal tract and patches of dark skin on various areas of the body. Some affected individuals have a skin condition called
urticaria pigmentosa (also known as cutaneous mastocytosis), which is characterized by raised patches of brownish skin that sting or
itch when touched.
Hereditary parapanglioma-pheochromocytoma
More than 150 mutations in the SDHB gene have been identified in people with hereditary paraganglioma-pheochromocytoma type 4.
People with this condition have paragangliomas, pheochromocytomas, or both. Paragangliomas and pheochromocytomas (a type of
paraganglioma) are noncancerous tumors associated with the nervous system. An inherited SDHB gene mutation predisposes an
individual to the condition, and a somatic mutation that deletes the normal copy of the gene is needed to cause hereditary
paraganglioma-pheochromocytoma type 4. Most of the inherited SDHB gene mutations change single protein building blocks (amino
acids) in the SDHB protein sequence or result in a shortened protein. As a result, there is little or no SDH enzyme activity. Because
the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. The excess succinate abnormally
stabilizes HIF, which also builds up in cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when
they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development
of tumors in people with hereditary paraganglioma-pheochromocytoma.
65
Nonsyndromic paraganglioma
Mutations in the SDHB gene are found in some cases of nonsyndromic paraganglioma or pheochromocytoma, which are nonhereditary forms of the condition. Most of these mutations change single amino acids in the SDHB protein. As in hereditary
paraganglioma-pheochromocytoma type 4, these mutations are expected to decrease SDH enzyme activity, which stabilizes the HIF
protein, causing it to build up in cells. Excess HIF protein abnormally stimulates cell division and the formation of blood vessels,
which can lead to tumor formation.
Other cancers
The SDHB gene is involved in several cancers. Mutations in the SDHB gene have been found in a small number of people with
gastrointestinal stromal tumors (GISTs), which are a type of tumor that occurs in the gastrointestinal tract, or renal cell carcinoma,
which is a type of kidney cancer. SDHB gene mutations have been identified in people a condition called Carney-Stratakis syndrome
in which affected individuals have both paraganglioma and GIST or in people with both renal cell cancer and paraganglioma. An
inherited SDHB gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of
the gene is needed to cause these forms of GIST, renal cell cancer, and paraganglioma. This second mutation, called a somatic
mutation, is acquired during a person's lifetime and is present only in tumor cells. Mutations of the SDHB gene lead to a reduction in
the amount of SDHB protein in the cell and loss of SDH enzyme activity. Furthermore, even without a SDHB gene mutation, a subset
of gastrointestinal stromal tumors have reduced SDHB protein and loss of SDH enzyme activity. Lack of SDH enzyme activity results
in abnormal hypoxia signaling and formation of tumors.
Health condition keywords
Cowden syndrome
Carney-Stratakis syndrome
Gastrointestinal stromal tumor
Hereditary parapanglioma-pheochromocytoma
Nonsyndromic paraganglioma
Gene: SDHC (succinate dehydrogenase complex subunit C)
Normal function
The SDHC gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH
enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells
can use. The SDHC protein helps anchor the SDH enzyme in the mitochondrial membrane. Within mitochondria, the SDH enzyme
links two important cellular pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As
part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively
charged particles called electrons are released during this reaction. The electrons are transferred through the SDH subunits, including
the SDHC protein, to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons help create an electrical
charge that provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source. Succinate, the
compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells
to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by
preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the
formation of new blood vessels in a hypoxic environment. The SDHC gene is a tumor suppressor, which means it prevents cells from
growing and dividing in an uncontrolled way.
Health conditions
Gastrointestinal stromal tumor
A gastrointestinal stromal tumor (GIST) is a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or
small intestine. The tumors are thought to grow from specialized cells found in the gastrointestinal tract called interstitial cells of Cajal
(ICCs) or precursors to these cells. GISTs are usually found in adults between ages 40 and 70; rarely, children and young adults
develop these tumors. The tumors can be cancerous (malignant) or noncancerous (benign). Affected individuals with no family history
of GIST typically have only one tumor (called a sporadic GIST). People with a family history of GISTs (called familial GISTs) often
have multiple tumors and additional signs or symptoms, including noncancerous overgrowth (hyperplasia) of other cells in the
gastrointestinal tract and patches of dark skin on various areas of the body. Some affected individuals have a skin condition called
urticaria pigmentosa (also known as cutaneous mastocytosis), which is characterized by raised patches of brownish skin that sting or
itch when touched.
Hereditary parapanglioma-pheochromocytoma
66
More than 30 mutations in the SDHC gene have been found to increase the risk of hereditary paraganglioma-pheochromocytoma type
3. People with this condition have paragangliomas, pheochromocytomas, or both. An inherited SDHC gene mutation predisposes an
individual to the condition, and a somatic mutation that deletes the normal copy of the SDHC gene is needed to cause hereditary
paraganglioma-pheochromocytoma type 3.
Most of the inherited SDHC gene mutations change single protein building blocks (amino acids) in the SDHC protein sequence or
result in a shortened protein. As a result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert
succinate to fumarate, succinate accumulates in the cell. The excess succinate abnormally stabilizes HIF, which also builds up in cells.
Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled
cell division, along with the formation of new blood vessels, can lead to the development of tumors in people with hereditary
paraganglioma-pheochromocytoma.
Other cancers
Mutations in the SDHC gene have been found in a small number of people with gastrointestinal stromal tumor (GIST), which is a
cancer of the gastrointestinal tract. SDHC gene mutations have also been identified in people with noncancerous tumors associated
with the nervous system called paragangliomas or pheochromocytomas (a type of paraganglioma). Some affected individuals have
both paraganglioma and GIST, which is called Carney-Stratakis syndrome. An inherited SDHC gene mutation predisposes an
individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause these forms of
GIST and paraganglioma. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only
in tumor cells.
Mutations of the SDHC gene lead to loss of SDH enzyme activity, which results in abnormal hypoxia signaling and formation of
tumors.
Health condition keywords
Carney-Stratakis syndrome
Gastrointestinal stromal tumor
Hereditary parapanglioma-pheochromocytoma
Gene: SDHD (succinate dehydrogenase complex subunit D)
Normal function
The SDHD gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH
enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells
can use. The SDHD protein helps anchor the SDH enzyme in the mitochondrial membrane. Within mitochondria, the SDH enzyme
links two important pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As part of the
citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively charged
particles called electrons are released during this reaction. The electrons are transferred through the SDH subunits, including the
SDHD protein, to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons create an electrical charge that
provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source. Succinate, the compound on which
the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a lowoxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by preventing a
reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the formation of
new blood vessels in a hypoxic environment.
The SDHD gene is a tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.
Health conditions
Cowden syndrome
At least five variants in the SDHD gene have been identified in people with Cowden syndrome or a similar disorder called Cowdenlike syndrome. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of
developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by SDHD gene mutations, the conditions
are associated with a particularly high risk of developing breast and thyroid cancers. The SDHD gene variants associated with Cowden
syndrome and Cowden-like syndrome change single amino acids in the SDHD protein, which likely alters the function of the SDH
enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked, leading to the formation of
hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHD gene variants are directly
associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely been found in
people without the features of these conditions.
67
Gastrointestinal stromal tumor
A gastrointestinal stromal tumor (GIST) is a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or
small intestine. The tumors are thought to grow from specialized cells found in the gastrointestinal tract called interstitial cells of Cajal
(ICCs) or precursors to these cells. GISTs are usually found in adults between ages 40 and 70; rarely, children and young adults
develop these tumors. The tumors can be cancerous (malignant) or noncancerous (benign). Affected individuals with no family history
of GIST typically have only one tumor (called a sporadic GIST). People with a family history of GISTs (called familial GISTs) often
have multiple tumors and additional signs or symptoms, including noncancerous overgrowth (hyperplasia) of other cells in the
gastrointestinal tract and patches of dark skin on various areas of the body. Some affected individuals have a skin condition called
urticaria pigmentosa (also known as cutaneous mastocytosis), which is characterized by raised patches of brownish skin that sting or
itch when touched.
Hereditary parapanglioma-pheochromocytoma
More than 100 mutations in the SDHD gene have been identified in people with hereditary paraganglioma-pheochromocytoma type 1.
People with this condition have paragangliomas, pheochromocytomas, or both. These noncancerous (benign) tumors are associated
with the nervous system. An inherited SDHD gene mutation predisposes an individual to the condition. An additional mutation that
deletes the normal copy of the gene is needed to cause hereditary paraganglioma-pheochromocytoma type 1. This second mutation,
called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells. Most of the inherited SDHD gene
mutations change single protein building blocks (amino acids) in the SDHD protein sequence or result in a shortened protein. As a
result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate
accumulates in the cell. The excess succinate abnormally stabilizes HIF, which also builds up in cells. Excess HIF stimulates cells to
divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the
formation of new blood vessels, can lead to the development of tumors in people with hereditary paraganglioma-pheochromocytoma.
Nonsyndromic paraganglioma
Mutations in the SDHD gene are found in some cases of nonsyndromic paraganglioma or pheochromocytoma, which are nonhereditary forms of the condition. Most of these mutations change single amino acids in the SDHD protein. As in hereditary
paraganglioma-pheochromocytoma type 1, these mutations are expected to decrease SDH enzyme activity, which stabilizes the HIF
protein, causing it to build up in cells. Excess HIF protein abnormally stimulates cell division and the formation of blood vessels,
which can lead to tumor formation.
Other cancers
Mutations in the SDHD gene have been found in a small number of people with Carney-Stratakis syndrome. People with this
condition have a type of cancer of the gastrointestinal tract called gastrointestinal stromal tumor (GIST) and a noncancerous tumor
associated with the nervous system called paraganglioma or pheochromocytoma (a type of paraganglioma). An inherited SDHD gene
mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to
cause Carney-Stratakis syndrome. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is
present only in tumor cells.
Mutations of the SDHD gene lead to loss of SDH enzyme activity, which results in abnormal hypoxia signaling and formation of
tumors.
Health condition keywords
Cowden syndrome
Carney-Stratakis syndrome
Gastrointestinal stromal tumor
Hereditary parapanglioma-pheochromocytoma
Nonsyndromic paraganglioma
Gene: SLX4 (SLX4 structure-specific endonuclease subunit)
Normal function
This gene encodes a structure-specific endonuclease subunit. The encoded protein contains a central BTB domain and it forms a
multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases, and also associates with
MSH2/MSH3 mismatch repair complex, telomere binding complex TERF2(TRF2)-TERF2IP(RAP1), the protein kinase PLK1 and the
uncharacterized protein C20orf94. The multiprotein complex is required for repair of specific types of DNA lesions and is critical for
cellular responses to replication fork failure. The encoded protein acts as a docking platform for the assembly of multiple structurespecific endonucleases.[provided by RefSeq, Jan 2011]1
68
Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases. Has several distinct roles
in protecting genome stability by resolving diverse forms of deleterious DNA structures originating from replication and
recombination intermediates and from DNA damage. Component of the SLX1-SLX4 structure-specific endonuclease that resolves
DNA secondary structures generated during DNA repair and recombination. Has endonuclease activity towards branched DNA
substrates, introducing single-strand cuts in duplex DNA close to junctions with ss-DNA. Has a preference for 5'-flap structures, and
promotes symmetrical cleavage of static and migrating Holliday junctions (HJs). Resolves HJs by generating two pairs of ligatable,
nicked duplex products. Interacts with the structure-specific ERCC4-ERCC1 endonuclease and promotes the cleavage of bubble
structures. Interacts with the structure-specific MUS81-EME1 endonuclease and promotes the cleavage of 3'-flap and replication forklike structures. SLX4 is required for recovery from alkylation-induced DNA damage and is involved in the resolution of DNA doublestrand breaks.2
Health conditions
Fanconi anemia
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical
abnormalities, organ defects, and an increased risk of certain cancers. More than half of people with Fanconi anemia have physical
abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or
café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi
anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and
other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped
eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the
reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile).
Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased
fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly). Individuals with Fanconi anemia have
an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors
of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with
Fanconi anemia is between 10 and 30 percent.
Fanconi anemia, complementation group P
A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac,
renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular
level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and
defective DNA repair. Some individuals affected by Fanconi anemia of complementation group P have skeletal anomalies.
[MIM:613951] 2
Tracheoesophageal fistula
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a condition resulting from abnormal development before birth of the tube
that carries food from the mouth to the stomach (the esophagus). During early development, the esophagus and windpipe (trachea)
begin as a single tube that normally divides into the two adjacent passages between four and eight weeks after conception. If this
separation does not occur properly, EA/TEF is the result. EA/TEF occurs alone (isolated EA/TEF) in about 40 percent of affected
individuals. In other cases it occurs with other birth defects or as part of a genetic syndrome (non-isolated or syndromic EA/TEF).
Health condition keywords
Fanconi anemia
Fanconi anemia, complementation group P
Tracheoesophageal fistula
Gene: SMAD4 (SMAD family member 4)
Normal function
The SMAD4 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the
nucleus. This signaling pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell
to affect how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches (binds) to a receptor on the
cell surface, which activates a group of related SMAD proteins. The SMAD proteins bind to the SMAD4 protein and form a protein
complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it
controls the activity of particular genes and regulates cell growth and division (proliferation). By controlling gene activity and
regulating cell proliferation, the SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors
69
help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled
way.
Health conditions
Hereditary hemorrhagic telangiectasia
At least five mutations in the SMAD4 gene have been found to cause a form of hereditary hemorrhagic telangiectasia called juvenile
polyposis/hereditary hemorrhagic telangiectasia syndrome. People with this disorder have the blood vessel problems associated with
hereditary hemorrhagic telangiectasia as well as an increased risk of developing intestinal growths (polyps) at an early age; the polyps
may become cancerous. SMAD4 gene mutations that cause this disorder affect the TGF-β signaling pathway. Disruption of this
pathway may interfere with both the tumor suppressor function of the SMAD4 protein and the appropriate development of the
boundaries between veins and arteries, resulting in the signs and symptoms of juvenile polyposis/hereditary hemorrhagic
telangiectasia syndrome
Juvenile polyposis syndrome
More than 60 mutations in the SMAD4 gene have been found to cause juvenile polyposis syndrome, a disorder characterized by
multiple noncancerous (benign) growths called juvenile polyps. Most SMAD4 gene mutations that cause juvenile polyposis syndrome
result in the production of an abnormally short, nonfunctional protein. A lack of functional SMAD4 protein prevents binding to other
SMAD proteins and interferes with the transmission of chemical signals from the cell surface to the nucleus. The SMAD protein
complex is not activated and cannot be transported to the nucleus, where it is needed to regulate cell proliferation and the activity of
certain genes. This unregulated cell growth can lead to polyp formation in people with juvenile polyposis syndrome.
Myhre syndrome
At least three mutations in the SMAD4 gene have been identified in people with Myhre syndrome, a condition with features including
intellectual disability, short stature, and hearing loss. Each of these mutations affects the protein building block (amino acid)
isoleucine at protein position 500 by replacing it with a different amino acid. Some researchers believe that the SMAD4 gene
mutations that cause Myhre syndrome impair the ability of the SMAD4 protein to bind properly with the other SMAD proteins and
other proteins involved in the signaling pathway. Other studies have suggested that these mutations result in an abnormally stable
SMAD4 protein that remains active in the cell longer. Changes in SMAD4 binding or availability may result in abnormal signaling in
many cell types, which affects development of many body systems and leads to the signs and symptoms of Myhre syndrome.
Other cancers
People with mutations in the SMAD4 gene appear to have an increased risk of developing various cancers. Some of these gene
mutations are inherited, while others are acquired during a person's lifetime. Such acquired (somatic) mutations are present only in
certain cells. Cells with mutations in the SMAD4 gene, whether inherited or somatic, may proliferate out of control and result in a
tumor, often in the colon or pancreas.
Other disorders
SMAD4 gene mutations have also been identified in a small number of individuals with juvenile polyposis and blood vessel
abnormalities other than hereditary hemorrhagic telangiectasia. These abnormalities include weakening and stretching (dilation) of the
aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Aortic dilation may lead to a bulge in
the blood vessel wall (an aneurysm), or may cause the aortic valve to leak, which can result in a sudden tearing of the layers in the
aorta wall (aortic dissection). Aortic aneurysm and dissection can be life-threatening. Impaired functioning of the mitral valve, which
connects two of the four chambers of the heart, has also been seen in combination with juvenile polyposis caused by SMAD4 gene
mutations.
Health condition keywords
Hereditary hemorrhagic telangiectasia
Juvenile polyposis syndrome
Myhre syndrome
Gene: SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin,
subfamily b, member 1)
Normal function
The SMARCB1 gene provides instructions for making a protein that forms one piece (subunit) of several different SWI/SNF protein
complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the
network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter
70
how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is
tightly packed, gene expression is lower than when DNA is loosely packed. Through their ability to regulate gene activity, SWI/SNF
complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the
growth, division, and maturation (differentiation) of cells. The SMARCB1 protein and other SWI/SNF subunits are thought to act as
tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.
The role of the SMARCB1 protein within the SWI/SNF complex is not completely understood.
Health conditions
Coffin-Siris syndrome
At least two mutations in the SMARCB1 gene can cause Coffin-Siris syndrome. This condition is characterized by delayed
development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. These
SMARCB1 gene mutations change or remove single protein building blocks (amino acids) in the SMARCB1 protein. Although it is
unclear how these changes affect SWI/SNF complexes, researchers suggest that SMARCB1 gene mutations result in abnormal
chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cellular processes, which
could explain the diverse signs and symptoms of Coffin-Siris syndrome. People with Coffin-Siris syndrome do not appear to have an
increased risk of cancer (see below).
Other disorders
Mutations in the SMARCB1 gene cause rhabdoid tumor predisposition syndrome (RTPS). Individuals with this condition have an
increased risk of developing aggressive cancerous growths called rhabdoid tumors, which form in the brain (often called atypical
teratoid/rhabdoid tumors) and in the kidney (often called malignant rhabdoid tumors). These tumors usually occur in infants and
young children. Some children with RTPS also develop schwannomas, which are noncancerous (benign) tumors of the nerve cells.
RTPS is caused by a single inherited mutation in the SMARCB1 gene that is present in cells throughout the body. An additional
mutation that deletes the normal copy of the gene is needed for tumors to develop. This second mutation, called a somatic mutation, is
acquired during a person's lifetime and is present only in tumor cells. In combination, the inherited and somatic mutations lead to the
absence of SMARCB1 protein. Somatic mutations in the SMARCB1 gene that result in the absence of SMARCB1 protein cause
noninherited (sporadic) rhabdoid tumors in children. The mechanism by which inherited or somatic SMARCB1 gene mutations lead to
rhabdoid tumors is unknown. Inherited SMARCB1 gene mutations can also cause schwannomatosis, which is characterized by the
development of multiple schwannomas. In contrast to gene mutations that cause rhabdoid tumors, these mutations are thought to lead
to production of an altered SMARCB1 protein that likely has some function. However, it is unclear how the altered protein leads to
development of schwannomas. It is likely that other genetic changes in addition to SMARCB1 gene mutations are necessary for
schwannoma development.
Health condition keywords
Coffin-Siris syndrome
Rhabdoid tumor predisposition syndrome
Schwannomatosis
Gene: STK11 (serine/threonine kinase 11)
Normal function
The STK11 gene (also called LKB1) provides instructions for making an enzyme called serine/threonine kinase 11. This enzyme is a
tumor suppressor, which means that it helps keep cells from growing and dividing too fast or in an uncontrolled way. This enzyme
helps certain types of cells correctly orient themselves within tissues (polarization) and assists in determining the amount of energy a
cell uses. This kinase also promotes a type of programmed cell death known as apoptosis. In addition to its role as a tumor suppressor,
serine/threonine kinase 11 function appears to be required for normal development before birth.
Health conditions
Breast cancer
Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although
breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most
common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands
that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. A small percentage
of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations.
Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors are more likely
to develop in both breasts. Inherited changes in the STK11 gene greatly increase the risk of developing breast cancer, as well as other
71
types of cancer, as part of Peutz-Jeghers syndrome (described above). These mutations are thought to account for only a small fraction
of all breast cancer cases.
Ovarian cancer
Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply
uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of
cases, ovarian cancer occurs after age 40, and most cases occur after age 60. Some ovarian cancers cluster in families. These cancers
are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life
than non-inherited (sporadic) cases. Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the
deaths of about 140,000 women annually, more than any other gynecological cancer. However, when it is diagnosed and treated early,
the 5-year survival rate is high.
Peutz-Jeghers syndrome
Inherited mutations in the STK11 gene cause Peutz-Jeghers syndrome, a condition characterized by the development of noncancerous
growths called hamartomatous polyps in the gastrointestinal tract and a greatly increased risk of developing several types of cancer.
More than 340 STK11 gene mutations have been identified in people with this condition. Many of these mutations result in the
production of an abnormally short, nonfunctional version of the serine/threonine kinase 11 enzyme. Other mutations change single
protein building blocks (amino acids) used to build the enzyme. Mutations in the STK11 gene impair the enzyme's tumor suppressor
function, allowing cells to grow and divide without control or order. This uncontrolled cell growth can lead to the formation of
hamartomatous polyps and cancerous tumors.
Other cancers
Noninherited (somatic) mutations in the STK11 gene have been found in various forms of cancer. Somatic mutations are acquired
during a person's lifetime and are present only in certain cells. They do not occur as part of a cancer syndrome. Somatic STK11 gene
mutations have been identified in a form of lung cancer called non-small cell lung carcinoma, cervical cancer, colorectal cancer, an
aggressive type of skin cancer called melanoma, and pancreatic cancer. These mutations impair the function of serine/threonine kinase
11, which can allow cells to grow and divide uncontrollably and contribute to the formation of a cancerous tumor.
Health condition keywords
Breast cancer
Colorectal cancer
Hereditary breast and ovarian cancer (HBOC)
Melanoma
Ovarian cancer
Pancreatic cancer
Peutz-Jeghers syndrome
Gene: SUFU (SUFU negative regulator of hedgehog signaling)
Normal function
The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays
a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog
signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript
variants.[provided by RefSeq, May 2010]1
Negative regulator in the hedgehog signaling pathway. Down-regulates GLI1-mediated transactivation of target genes
(PubMed:15367681, PubMed:24311597, PubMed:24217340). Down-regulates GLI2-mediated transactivation of target genes
(PubMed:24311597, PubMed:24217340). Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1
to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect
is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10806483, PubMed:24217340). Negative regulator of
beta-catenin signaling. Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full length
form of GLI3 (GLI3FL). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh
signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. When Hh signaling is
initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and
converted to a transcriptional activator (GLI3A). Required for normal embryonic development. Required for the proper formation of
hair follicles and the control of epidermal differentiation.2
72
Health conditions
Gorlin syndrome
Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is a condition that affects many areas of the body and
increases the risk of developing various cancerous and noncancerous tumors. In people with Gorlin syndrome, the type of cancer
diagnosed most often is basal cell carcinoma, which is the most common form of skin cancer. Individuals with Gorlin syndrome
typically begin to develop basal cell carcinomas during adolescence or early adulthood. These cancers occur most often on the face,
chest, and back. The number of basal cell carcinomas that develop during a person's lifetime varies among affected individuals. Some
people with Gorlin syndrome never develop any basal cell carcinomas, while others may develop thousands of these cancers.
Individuals with lighter skin are more likely to develop basal cell carcinomas than are people with darker skin. Individuals with Gorlin
syndrome have a higher risk than the general population of developing other tumors. A small proportion of affected individuals
develop a brain tumor called medulloblastoma during childhood. A type of benign tumor called a fibroma can occur in the heart or in a
woman's ovaries. Heart (cardiac) fibromas often do not cause any symptoms, but they may obstruct blood flow or cause irregular
heartbeats (arrhythmia). Ovarian fibromas are not thought to affect a woman's ability to have children (fertility). Other features of
Gorlin syndrome include small depressions (pits) in the skin of the palms of the hands and soles of the feet; an unusually large head
size (macrocephaly) with a prominent forehead; and skeletal abnormalities involving the spine, ribs, or skull. These signs and
symptoms are typically apparent from birth or become evident in early childhood.
Medulloblastoma
Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[MIM:15525] 2
Health condition keywords
Gorlin syndrome
Medulloblastoma
Gene: TMEM127 (transmembrane protein 127)
Normal function
The TMEM127 gene provides instructions for making a protein that acts as a tumor suppressor protein, which means it prevents cells
from growing and dividing too quickly or in an uncontrolled way. The TMEM127 protein controls a signaling pathway that leads to
cell growth and survival. Research shows that this pathway, regulated by a protein complex called mTORC1, is blocked (inhibited) by
the TMEM127 protein, although the specific action of the TMEM127 protein is unknown.
Health conditions
Nonsyndromic paraganglioma
Mutations in the TMEM127 gene increase the risk of developing a noncancerous tumor associated with the nervous system called
paraganglioma or pheochromocytoma (a type of paraganglioma). TMEM127 gene mutations occur most commonly in people with
pheochromocytoma, and they are rarely found in people with other paraganglioma. Specifically, TMEM127 gene mutations are
associated with nonsyndromic paraganglioma or pheochromocytoma, which means the tumors occur without additional features of an
inherited syndrome. At least 19 TMEM127 gene mutations have been identified in people with one of these tumors. A TMEM127 gene
mutation increases the risk of tumor formation. The TMEM127 gene mutations associated with paraganglioma or pheochromocytoma
change single protein building blocks (amino acids) in the TMEM127 protein sequence or result in a shortened protein.
Most people with TMEM127-related paraganglioma or pheochromocytoma acquire an additional mutation that deletes the normal
copy of the gene. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor
cells. Together, the two mutations lead to reduced or absent TMEM127 protein. As a result, the cell growth pathway controlled by the
TMEM127 protein is abnormally active, leading to tumor formation.
Health condition keyword
Nonsyndromic paraganglioma
Gene: TP53 (tumor protein p53)
Normal function
The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor,
which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. The p53
protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell
73
becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role
in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be
repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and
signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of
tumors. Because p53 is essential for regulating cell division and preventing tumor formation, it has been nicknamed the "guardian of
the genome."
Health conditions
Bladder cancer
Somatic TP53 gene mutations have been found in some cases of bladder cancer. Most of these mutations change single amino acids in
p53. The altered protein cannot bind to DNA, preventing it from effectively regulating cell growth and division. As a result, DNA
damage accumulates in cells, which can allow them to grow and divide in an uncontrolled way to form a cancerous tumor. Mutations
in the TP53 gene may help predict whether bladder cancer will progress and spread to nearby tissues, and whether the disease will
recur after treatment.
Breast cancer
Inherited changes in the TP53 gene greatly increase the risk of developing breast cancer, as well as several other forms of cancer, as
part of a rare cancer syndrome called Li-Fraumeni syndrome (described below). These mutations are thought to account for only a
small fraction of all breast cancer cases.
Noninherited (somatic) mutations in the TP53 gene are much more common than inherited mutations, occurring in 20 to 40 percent of
all breast cancers. These somatic mutations are acquired during a person's lifetime and are present only in cells that become cancerous.
The cancers associated with somatic mutations do not occur as part of a cancer syndrome. Most of these mutations change single
protein building blocks (amino acids) in the p53 protein, which reduces or eliminates the protein's tumor suppressor function. Because
the altered protein is less able to regulate cell growth and division, DNA damage can accumulate. This damage may contribute to the
development of a cancerous tumor by allowing cells to grow and divide in an uncontrolled way. Compared with breast cancers
without TP53 gene mutations, tumors with these genetic changes tend to have a poorer prognosis. They are more likely to be
aggressive, to be resistant to treatment with certain anti-cancer drugs and radiation, and to come back (recur) after treatment.
Head and neck squamous cell carcinoma
Somatic mutations in the TP53 gene have been found in nearly half of all head and neck squamous cell carcinomas (HNSCC). This
type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. Most of the TP53 gene mutations involved in
HNSCC change single amino acids in p53; these changes impair the protein's function. Without functioning p53, DNA damage builds
up in cells, and they can continue to divide without control, leading to tumor formation.
Li-Fraumeni syndrome
Although somatic mutations in the TP53 gene are found in many types of cancer, Li-Fraumeni syndrome appears to be the only cancer
syndrome associated with inherited mutations in this gene. This condition greatly increases the risk of developing several types of
cancer, particularly in children and young adults. At least 140 different mutations in the TP53 gene have been identified in individuals
with Li-Fraumeni syndrome. Many of the mutations associated with Li-Fraumeni syndrome change single amino acids in the part of
the p53 protein that binds to DNA. Other mutations delete small amounts of DNA from the gene. Mutations in the TP53 gene lead to a
version of p53 that cannot regulate cell growth and division effectively. Specifically, the altered protein is unable to trigger apoptosis
in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an
uncontrolled way, leading to the growth of tumors.
Ovarian cancer
Somatic TP53 gene mutations are common in ovarian cancer, occurring in almost half of ovarian tumors. These mutations result in a
p53 protein that is less able to control cell growth and division, contributing to the development of a cancerous tumor.
Other cancers
Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all
cancers. In addition to the cancers described above, somatic TP53 gene mutations have been identified in several types of brain tumor,
colorectal cancer, liver cancer, lung cancer, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called
rhabdomyocarcinoma, and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormoneproducing glands on top of each kidney).
Most TP53 mutations change single amino acids in the p53 protein, which leads to the production of an altered version of the protein
that cannot control cell growth and division effectively. As a result, cells can grow and divide in an unregulated way, which can lead
to cancerous tumors.
74
Health condition keywords
Bladder cancer
Breast cancer
Head and neck squamous cell carcinoma
Hereditary breast and ovarian cancer (HBOC)
Li-Fraumeni syndrome
Ovarian cancer
Gene: TSC1 (tuberous sclerosis 1)
Normal function
The TSC1 gene provides instructions for producing a protein called hamartin, whose function is not fully understood. Within cells,
hamartin interacts with a protein called tuberin, which is produced from the TSC2 gene. These two proteins help control cell growth
and size. Proteins that normally prevent cells from growing and dividing too fast or in an uncontrolled way are known as tumor
suppressors. Hamartin and tuberin carry out their tumor suppressor function by interacting with and regulating a wide variety of other
proteins.
Health conditions
Bladder cancer
Somatic mutations of the TSC1 gene that occur in bladder cells are associated with some cases of bladder cancer. In some of these
cells, one copy of the TSC1 gene is missing because the region of chromosome 9 containing the gene has been deleted; the other copy
of the gene has a mutation that interferes with its function. As a result, little or no hamartin is produced. A loss of hamartin in bladder
cells may allow these cells to grow and divide without control, leading to the formation of a cancerous tumor. It is unclear why
inherited TSC1 gene mutations lead to the noncancerous growths characteristic of tuberous sclerosis complex, while somatic
mutations in this gene are associated with the development of cancerous tumors.
Lymphangioleiomyomatosis
Mutations in the TSC1 gene can cause a disorder called lymphangioleiomyomatosis (LAM), although mutations in the TSC2 gene
appear to be responsible for most cases of this disorder. This destructive lung disease is caused by the abnormal overgrowth of smooth
muscle-like tissue in the lungs. It occurs almost exclusively in women, causing coughing, shortness of breath, chest pain, and lung
collapse.
LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described
below). Researchers suggest that sporadic LAM can be caused by a random mutation in the TSC1 gene that occurs very early in
development. As a result, some of the body's cells have a normal version of the gene, while others have the mutated version. This
situation is called mosaicism. When a mutation occurs in the other copy of the TSC1 gene in certain cells during a woman's lifetime (a
somatic mutation), she may develop LAM.
Tuberous sclerosis complex
More than 400 mutations in the TSC1 gene have been identified in individuals with tuberous sclerosis complex, a condition
characterized by developmental problems and the growth of noncancerous tumors in many parts of the body. Most of these mutations
involve either small deletions or insertions of DNA in the TSC1 gene. Some mutations create a premature stop signal in the
instructions for making hamartin. People with TSC1-related tuberous sclerosis complex are born with one mutated copy of the TSC1
gene in each cell. This mutation prevents the cell from making functional hamartin from that copy of the gene. However, enough
hamartin is usually produced from the other, normal copy of the TSC1 gene to regulate cell growth effectively. For some types of
tumors to develop, a second mutation involving the other copy of the gene must occur in certain cells during a person's lifetime.
When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin. The loss of this
protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of hamartin also interferes with the
normal development of certain cells. In people with TSC1-related tuberous sclerosis complex, a second TSC1 gene mutation typically
occurs in multiple cells over an affected person's lifetime. The loss of hamartin in different types of cells disrupts normal development
and leads to the growth of tumors in many different organs and tissues.
Other disorders
Inherited mutations in the TSC1 gene can cause a disorder known as focal cortical dysplasia of Taylor balloon cell type. This disorder
involves malformations of the cerebrum, the large, frontal part of the brain that is responsible for thinking and learning. Focal cortical
dysplasia causes severe recurrent seizures (epilepsy) in affected individuals.
75
Health condition keywords
Bladder cancer
Lymphangioleiomyomatosis
Tuberous sclerosis complex
Focal cortical dysplasia of Taylor balloon cell type
Gene: TSC2 (tuberous sclerosis 2)
Normal function
The TSC2 gene provides instructions for producing a protein called tuberin, whose function is not fully understood. Within cells,
tuberin interacts with a protein called hamartin, which is produced from the TSC1 gene. These two proteins help control cell growth
and size. Proteins that normally prevent cells from growing and dividing too fast or in an uncontrolled way are known as tumor
suppressors. Hamartin and tuberin carry out their tumor suppressor function by interacting with and regulating a wide variety of other
proteins.
Health conditions
Lymphangioleiomyomatosis
Mutations in the TSC2 gene cause most cases of a disorder called lymphangioleiomyomatosis (LAM). This destructive lung disease is
characterized by the abnormal overgrowth of smooth muscle-like tissue in the lungs. It occurs almost exclusively in women, causing
coughing, shortness of breath, chest pain, and lung collapse.
LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described
below). Researchers suggest that sporadic LAM is caused by a random mutation in the TSC2 gene that occurs very early in
development. As a result, some of the body's cells have a normal version of the gene, while others have the mutated version. This
situation is called mosaicism. When a mutation occurs in the other copy of the TSC2 gene in certain cells during a woman's lifetime (a
somatic mutation), she may develop LAM.
Tuberous sclerosis complex
More than 1,100 mutations in the TSC2 gene have been identified in individuals with tuberous sclerosis complex, a condition
characterized by developmental problems and the growth of noncancerous tumors in many parts of the body. Most of these mutations
insert or delete a small number of DNA building blocks (base pairs) in the TSC2 gene. Other mutations change a single base pair in
the TSC2 gene or create a premature stop signal in the instructions for making tuberin. People with TSC2-related tuberous sclerosis
complex are born with one mutated copy of the TSC2 gene in each cell. This mutation prevents the cell from making functional
tuberin from that copy of the gene. However, enough tuberin is usually produced from the other, normal copy of the TSC2 gene to
regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the gene must
occur in certain cells during a person's lifetime. When both copies of the TSC2 gene are mutated in a particular cell, that cell cannot
produce any functional tuberin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A
shortage of tuberin also interferes with the normal development of certain cells. In people with TSC2-related tuberous sclerosis
complex, a second TSC2 gene mutation typically occurs in multiple cells over an affected person's lifetime. The loss of tuberin in
different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues.
Health condition keywords
Lymphangioleiomyomatosis
Tuberous sclerosis complex
Gene: VHL (von Hippel-Lindau tumor suppressor)
Normal function
The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together)
called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer
needed. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal
functions of cells. One of the targets of the VCB-CUL2 complex is a protein called hypoxia-inducible factor 2-alpha (HIF-2α). HIF-2α
is one part (subunit) of a larger protein complex called HIF, which plays a critical role in the body's ability to adapt to changing
oxygen levels. HIF controls several genes involved in cell division, the formation of new blood vessels, and the production of red
blood cells. It is the major regulator of a hormone called erythropoietin, which controls red blood cell production. HIF's function is
particularly important when oxygen levels are lower than normal (hypoxia). However, when adequate oxygen is available, the VCBCUL2 complex keeps HIF from building up inappropriately in cells.
76
The VHL protein likely plays a role in other cellular functions, including the regulation of other genes and control of cell division.
Based on this function, the VHL protein is classified as a tumor suppressor, which means it prevents cells from growing and dividing
too rapidly or in an uncontrolled way. The VHL protein is also involved in the formation of the extracellular matrix, which is an
intricate lattice that forms in the spaces between cells and provides structural support to tissues.
Health conditions
Familial erythrocytosis
At least 10 inherited mutations in the VHL gene have been found to cause familial erythrocytosis, a condition characterized by an
increased number of red blood cells and an elevated risk of abnormal blood clots. When familial erythrocytosis results from VHL gene
mutations, it is often designated ECYT2. The first VHL gene mutation related to familial erythrocytosis was identified in the Chuvash
population of Russia. (It has since been found in other geographic regions as well.) The mutation changes a single protein building
block (amino acid) in the VHL protein, replacing the amino acid arginine with the amino acid tryptophan at position 200 (written as
Arg200Trp or R200W). This mutation disrupts the function of the VHL protein, particularly its ability to target HIF-2α to be broken
down. As a result, HIF accumulates in cells even when adequate oxygen is available. The presence of extra HIF leads to the
production of red blood cells when no more are needed, which leads to an excess of these cells in the bloodstream. The other VHL
gene mutations that can cause familial erythrocytosis also change single amino acids in the VHL protein. These genetic changes are
thought to have similar effects on protein function to those of the Arg200Trp mutation. These mutations have been identified in the
Chuvash population and in other regions worldwide.
Nonsyndromic paraganglioma
Mutations in the VHL gene increase the risk of developing tumors of the nervous system called paragangliomas or
pheochromocytomas (a type of paraganglioma). Pheochromocytomas are a feature of von Hippel-Lindau syndrome, but they and other
paragangliomas can also occur nonsyndromically (without the other signs and symptoms of the syndrome). VHL gene mutations
associated with nonsyndromic paraganglioma or pheochromocytoma can be inherited or can occur spontaneously. Some spontaneous
mutations associated with this condition occur during the formation of reproductive cells (eggs or sperm) or just after fertilization and
are called de novo mutations. This type of mutation is found in every cell of the body. Other spontaneous mutations found in this
condition, called somatic mutations, are acquired during a person's lifetime and are present only in the tumor cells. The VHL gene
mutations found in nonsyndromic paraganglioma or pheochromocytoma change single amino acids in the VHL protein or create an
abnormally short protein. These changes disrupt the function of the protein. As in von Hippel-Lindau syndrome, when the VHL
protein is altered, the HIF-2α protein is not broken down, and instead builds up in cells. Excess HIF stimulates cells to divide
abnormally and triggers the production of blood vessels when they are not needed, which can lead to the development of
paraganglioma or pheochromocytoma.
von Hippel-Lindau syndrome
More than 370 inherited mutations in the VHL gene have been identified in people with von Hippel-Lindau syndrome, a disorder
characterized by the formation of tumors and fluid-filled sacs (cysts) in many different parts of the body. VHL gene mutations
associated with this condition either prevent the production of any VHL protein or lead to the production of an abnormal version of the
protein. When the VHL protein is altered or missing, the VCB-CUL2 complex cannot target HIF-2α and other proteins to be broken
down. As a result, HIF can build up in cells. Excess HIF stimulates cells to divide abnormally and triggers the production of blood
vessels when they are not needed. Rapid and uncontrolled cell division, along with the abnormal formation of new blood vessels, can
lead to the development of cysts and tumors in people with von Hippel-Lindau syndrome.
Other cancers
Somatic (noninherited) mutations in the VHL gene are associated with a form of kidney cancer called clear cell renal cell carcinoma.
This type of cancer is described as sporadic when it develops in people without inherited VHL mutations. Instead of occurring in every
cell in the body, somatic VHL mutations occur only in certain kidney cells. These genetic changes prevent the cells from producing
functional VHL protein. A lack of this protein allows the cells to grow and divide abnormally, which may contribute to the
development of sporadic kidney tumors. In addition, somatic mutations in the VHL gene in kidney cells may promote the growth of
existing kidney tumors.
Other disorders
Mutations in the VHL gene have been identified in a type of tumor called a hemangioblastoma. These tumors are made of newly
formed blood vessels and tend to develop in the brain and spinal cord. Hemangioblastomas are a characteristic feature of von HippelLindau syndrome, but they can also occur sporadically (without the other signs and symptoms of that condition). When these tumors
develop in people without von Hippel-Lindau syndrome, they are associated with somatic mutations in the VHL gene. The somatic
mutations associated with hemangioblastomas are acquired during a person's lifetime and are present only in the cells that give rise to
blood and blood vessels.
It is unclear how inherited and somatic mutations in the VHL gene are associated with such a wide variety of different conditions.
77
Health condition keywords
Familial erythrocytosis
Nonsyndromic paraganglioma
von Hippel-Lindau syndrome
Gene: WRN (Werner syndrome RecQ like helicase)
Normal function
The WRN gene provides instructions for producing the Werner protein, which plays a critical role in repairing damaged DNA. The
Werner protein functions as a type of enzyme called a helicase. Helicase enzymes generally unwind and separate double-stranded
DNA. The Werner protein also functions as an enzyme called an exonuclease. Exonucleases trim the broken ends of damaged DNA
by removing DNA building blocks (nucleotides). Research suggests that the Werner protein first unwinds the DNA and then removes
abnormal DNA structures that have been accidentally generated. Overall, the Werner protein helps maintain the structure and integrity
of a person's DNA. This protein plays an important role in copying (replicating) DNA before cell division and transferring the
information in genes to the cell machinery that makes proteins (transcription). Additionally, recent studies suggest that the Werner
protein may be particularly important for maintaining DNA at the ends of chromosomes (telomeres).
Health conditions
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
Werner syndrome
More than 60 mutations in the WRN gene are known to cause Werner syndrome. Most of these mutations result in an abnormally
short, nonfunctional Werner protein. Research suggests that this shortened protein is not transported into the cell's nucleus, where it
normally interacts with DNA. Furthermore, the shortened protein is broken down more quickly than the normal Werner protein,
reducing the amount of this protein in the cell. Without normal Werner protein in the nucleus, DNA replication, repair, and
transcription are disrupted. Researchers are still determining how mutations in the WRN gene lead to the signs and symptoms of
Werner syndrome.
Other cancers
Some changes to a person's genes are acquired during that person's lifetime and are present only in certain cells. These differences,
called somatic changes, are not inherited. Somatic changes in the WRN gene are found in nonhereditary tumors and involve a process
called methylation. Methylation is a chemical modification that attaches small molecules called methyl groups to certain segments of
DNA. When too many methyl groups are attached to the WRN gene (hypermethylation), the gene is turned off and the Werner protein
is not produced. Without this protein, cells do not respond normally to DNA damage. The lack of Werner protein allows mutations to
accumulate in other genes, which may cause cells to grow and divide in an uncontrolled way. This kind of unregulated cell growth can
lead to the formation of cancerous tumors. Hypermethylation of the WRN gene has been found in many different types of tumors,
including colon, rectal, lung, stomach, prostate, breast, and thyroid tumors.
Health condition keywords
Prostate cancer
Werner syndrome
Gene: WT1 (Wilms tumor 1)
Normal function
The WT1 gene provides instructions for making a protein that is necessary for the development of the kidneys and gonads (ovaries in
females and testes in males). Within these tissues, the WT1 protein plays a role in cell growth, the process by which cells mature to
perform specific functions (cell differentiation), and the self-destruction of cells (apoptosis). To carry out these functions, the WT1
protein regulates the activity of other genes by attaching (binding) to specific regions of DNA. On the basis of this action, the WT1
protein is called a transcription factor.
78
Health conditions
Cytogenetically normal acute myeloid leukemia
Cytogenetically normal acute myeloid leukemia (CN-AML) is one form of a cancer of the blood-forming tissue (bone marrow) called
acute myeloid leukemia. In normal bone marrow, early blood cells called hematopoietic stem cells develop into several types of blood
cells: white blood cells (leukocytes) that protect the body from infection, red blood cells (erythrocytes) that carry oxygen, and platelets
(thrombocytes) that are involved in blood clotting. In acute myeloid leukemia, the bone marrow makes large numbers of abnormal,
immature white blood cells called myeloid blasts. Instead of developing into normal white blood cells, the myeloid blasts develop into
cancerous leukemia cells. The large number of abnormal cells in the bone marrow interferes with the production of functional white
blood cells, red blood cells, and platelets. The age at which CN-AML begins ranges from childhood to late adulthood. CN-AML is
said to be an intermediate-risk cancer because the prognosis varies: some affected individuals respond well to normal treatment while
others may require stronger treatments. The age at which the condition begins and the prognosis are affected by the specific genetic
factors involved in the condition.
Denys-Drash syndrome
At least 80 mutations in the WT1 gene have been found to cause Denys-Drash syndrome, a condition that affects development of the
kidneys and genitalia and most often affects males. These mutations almost always occur in areas of the gene known as exon 8 and
exon 9. Most mutations change single protein building blocks (amino acids) in the WT1 protein. The most common mutation that
causes Denys-Drash syndrome (found in about 40 percent of cases) replaces the amino acid arginine with the amino acid tryptophan at
protein position 394 (written Arg349Trp or R349W). The mutations that cause Denys-Drash syndrome lead to the production of an
abnormal WT1 protein that cannot bind to DNA. As a result, the activity of certain genes is unregulated, which impairs development
of the kidneys and genitalia. Abnormal development of these organs leads to the signs and symptoms of Denys-Drash syndrome.
Rarely, a mutation in exon 8 or exon 9 of the WT1 gene causes a related condition called Frasier syndrome (described below). Because
these two conditions share a genetic cause and have overlapping features, some researchers have suggested that these two conditions
are part of a spectrum and not two distinct conditions.
Frasier syndrome
At least seven mutations in the WT1 gene have been found to cause Frasier syndrome, a condition that affects development of the
kidneys and genitalia and most often affects males. These mutations almost always occur in an area of the gene known as intron 9.
The most common mutation that causes Frasier syndrome (found in over half of affected individuals) changes a single DNA building
block (nucleotide) in the WT1 gene, written as IVS+4C>T. This mutation and others that cause Frasier syndrome alter the way the
gene's instructions are pieced together to produce the protein. The WT1 gene mutations that cause Frasier syndrome lead to the
production of a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive
organs, resulting in the signs and symptoms of Frasier syndrome. Rarely, a mutation in intron 9 of the WT1 gene causes a related
condition called Denys-Drash syndrome (described above). Because these two conditions share a genetic cause and have overlapping
features, some researchers have suggested that these two conditions are part of a spectrum and not two distinct conditions.
Prostate cancer
Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate
become abnormal and multiply without control or order to form a tumor. The prostate is a gland that surrounds the male urethra and
helps produce semen, the fluid that carries sperm. A small percentage of all prostate cancers cluster in families. These hereditary
cancers are associated with inherited gene mutations. Hereditary prostate cancers tend to develop earlier in life than non-inherited
(sporadic) cases.
WAGR syndrome
The WT1 gene is located in a region of chromosome 11 that is often deleted in people with WAGR syndrome, which is a disorder that
affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor, an eye problem
called anirida, genitourinary anomalies, and intellectual disability (formerly referred to as mental retardation). As a result of this
deletion, affected individuals are missing one copy of the WT1 gene in each cell. The loss of this gene is responsible for the
genitourinary abnormalities and the increased risk of Wilms tumor in affected individuals.
Other cancers
Mutations in the WT1 gene can cause Wilms tumor, a rare form of kidney cancer that usually occurs in early childhood. Some people
with Wilms tumor have a mutation in one copy of the WT1 gene in every cell. Most of these are new mutations that occur during the
formation of reproductive cells (eggs and sperm) or in early fetal development, although some may be inherited from a parent. In other
people with Wilms tumor, WT1 gene mutations are present only in the tumor cells. These changes are typically somatic, which means
they are acquired during a person's lifetime. WT1 gene mutations, whether they are somatic or present in every cell, account for 10 to
20 percent of cases of Wilms tumor. Changes in the activity (expression) of the WT1 gene are associated with several other forms of
cancer. In particular, the WT1 gene is abnormally expressed in certain types of lung, prostate, breast, and ovarian cancer. Abnormal
79
expression of the WT1 gene also occurs in some cancers of blood-forming cells (leukemias), such as acute lymphoblastic leukemia
(ALL), chronic myeloid leukemia (CML), and childhood acute myeloid leukemia (AML). It is unclear what role the WT1 protein
plays in the development or progression of cancer.
Other disorders
At least two mutations in the WT1 gene have been found to cause Meacham syndrome. This condition is characterized by
abnormalities in the development of the male genitalia, heart, and diaphragm. Individuals with this condition have a typical male
chromosome pattern (46,XY) but have external genitalia that do not look clearly male or clearly female (ambiguous genitalia) or have
genitalia that appear completely female. Additionally, the internal reproductive organs are female, but they do not develop normally.
Individuals with Meacham syndrome typically have heart defects that are present from birth and can vary in severity. They also have a
hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a congenital diaphragmatic
hernia. Meacham syndrome is typically fatal in infancy. Approximately a dozen individuals have been described as affected with
Meacham syndrome. Mutations in the WT1 gene can also cause a condition called isolated nephrotic syndrome. This condition is
characterized by an inability of the kidneys to filter waste products from blood, which leads to protein in the urine, swelling (edema),
and ultimately, kidney failure. Isolated nephrotic syndrome includes diffuse glomerulosclerosis, in which scar tissue forms throughout
the clusters of tiny blood vessels (glomeruli) in the kidneys, and focal segmental glomerulosclerosis, in which glomeruli in only
certain areas of the kidneys experience scarring. Mutations in the WT1 gene most often cause diffuse glomerulosclerosis
Health condition keywords
Cytogenetically normal acute myeloid leukemia
Denys-Drash syndrome
Frasier syndrome
Kidney cancer
Prostate cancer
WAGR syndrome
Gene: XPA (xeroderma pigmentosum, complementation group A)
Normal function
The XPA gene provides instructions for making a protein that is involved in repairing damaged DNA. DNA can be damaged by
ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. DNA damage occurs
frequently, but normal cells are usually able to fix it before it can cause problems. One of the major mechanisms that cells use to fix
DNA is known as nucleotide excision repair (NER). As part of this repair mechanism, the XPA protein helps verify DNA damage and
stabilize the DNA as it is repaired. The XPA protein attaches (binds) to areas of damaged DNA, where it interacts with many other
proteins as part of a large complex. Proteins in this complex unwind the section of DNA where the damage has occurred, snip out
(excise) the abnormal section, and replace the damaged area with the correct DNA.
Health conditions
Xeroderma pigmentosum
At least 25 mutations in the XPA gene have been found to cause xeroderma pigmentosum. Mutations in this gene are responsible for a
very severe form of the disorder that is more common in the Japanese population than in other populations. Most Japanese people with
xeroderma pigmentosum have the same XPA gene mutation, which is written as IVS3AS, G>C. This mutation prevents cells from
producing any functional XPA protein. Other XPA gene mutations, which have been reported in Japan and elsewhere, result in the
production of a defective version of the XPA protein or greatly reduce the amount of this protein that is made in cells. A partial or
total loss of the XPA protein prevents cells from repairing DNA damage normally. As a result, abnormalities accumulate in DNA,
causing cells to malfunction and eventually to become cancerous or die. These problems with DNA repair cause people with
xeroderma pigmentosum to be extremely sensitive to UV rays from sunlight. When UV rays damage genes that control cell growth
and division, cells can grow too fast and in an uncontrolled way. As a result, people with xeroderma pigmentosum have a greatly
increased risk of developing cancer. These cancers occur most frequently in areas of the body that are exposed to the sun, such as the
skin and eyes. When xeroderma pigmentosum is caused by XPA gene mutations, it is often associated with progressive neurological
abnormalities. These nervous system problems include hearing loss, poor coordination, difficulty walking, movement problems, loss
of intellectual function, difficulty swallowing and talking, and seizures. The neurological abnormalities are thought to result from a
buildup of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve
cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.
Health condition keywords
Xeroderma pigmentosum
80
Gene: XPC (xeroderma pigmentosum, complementation group C)
Normal function
The XPC gene provides instructions for making a protein that is involved in repairing damaged DNA. DNA can be damaged by
ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. DNA damage occurs
frequently, but normal cells are usually able to fix it before it can cause problems. One of the major mechanisms that cells use to fix
DNA is known as nucleotide excision repair (NER). The XPC protein starts this repair process by detecting DNA damage. Then a
group (complex) of other proteins unwind the section of DNA where the damage has occurred, snip out (excise) the abnormal section,
and replace the damaged area with the correct DNA. Studies suggest that the XPC protein may have additional roles in DNA repair
and in other cell activities. Less is known about these proposed functions of the XPC protein.
Health conditions
Xeroderma pigmentosum
More than 40 mutations in the XPC gene have been found to cause xeroderma pigmentosum. Mutations in this gene are the most
common cause of this disorder in the United States and Europe.
Most XPC gene mutations prevent the production of any XPC protein. A loss of this protein keeps cells from repairing DNA damage
normally. As a result, abnormalities accumulate in DNA, causing cells to malfunction and eventually to become cancerous or die.
These problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays from sunlight.
When UV rays damage genes that control cell growth and division, cells can grow too fast and in an uncontrolled way. As a result,
people with xeroderma pigmentosum have a greatly increased risk of developing cancer. These cancers occur most frequently in areas
of the body that are exposed to the sun, such as the skin and eyes.
Unlike some of the other forms of xeroderma pigmentosum, when the disorder is caused by mutations in the XPC gene it is generally
not associated with neurological abnormalities (such as delayed development and hearing loss). It is unclear why some people with
xeroderma pigmentosum develop neurological abnormalities and others do not.
Health condition keywords
Xeroderma pigmentosum
81
INDEX1:HEALTHCONDITIONKEYWORDGLOSSARY
HealthCondition
Page
9q22.3microdeletion
55
Ataxia-telangiectasia
8
Baller-Geroldsyndrome
Bannayan-Riley-Ruvalcabasyndrome
61
56-57
Beckwith-Wiedemannsyndrome
17
Birt-Hogg-Dubesyndrome
37
Bladdercancer
8,40,60,74,75
Bonecancer
20,60,74
Braincancer
20
8,10,11,12,13,15-20,29,38,45,47-48,50-51,55-60,
65,71-72,74-75
Breastcancer
Brooke-Spieglersyndrome
Café-au-laitspots
Cancersoftheblood
Carneycomplex
Carney-Stratakissyndrome
Cockaynesyndrome
Coffin-Sirissyndrome
Colorectalcancer
20-21
11-12,35,45-46,51,53,58,69
45-46,53
54
66-68
26-27
71
7,10,11,20,45,46,47,52,53,57,72,74
Congenitalcentralhypoventilationsyndrome
52
Congenitalhyperinsulinism
39
Congenitaltuftingenteropathy
24
Corebindingfactoracutemyeloidleukemia
41,63-64
Costellosyndrome
40
Cowdensyndrome
56-57,65-68
Cutaneousmalignantmelanoma3
Cutaneousmelanoma
Cytogeneticallynormalacutemyeloidleukemia
Dendriticcell,monocyte,Blymphocyteandnaturalkiller
lymphocytedeficiency
Denys-Drashsyndrome
Desmoidtumor
16
8-9
18,63-64,79-80
38
79-80
7
Diabetesmellitustype1-2
39
Diabetesmellitus,insulin-dependent,20
39
DICER1syndrome
22
FamilialacutemyeloidleukemiawithmutatedCEBPA
18
Familialadenomatouspolyposis
Familialcancerofbreast
Familialcylindromatosis
Familialerythrocytosis
Familialhemophagocyticlymphohistiocytosis
Familialisolatedacromegaly
7,47
12
21
77-78
54
5
82
HealthCondition
Familialisolatedhyperparathyroidism
Familialisolatedpituitaryadenoma(FIPA)
Fanconianemia
FanconianemiacomplementationgroupB
Page
14,42-43
5
11-13,26-27,30-36,51,58-59,69
30-31
FanconianemiacomplementationgroupD2
31-32
FanconianemiacomplementationgroupG
33-34
FanconianemiacomplementationgroupI
34
FanconianemiacomplementationgroupL
34-35
FanconianemiacomplementationgroupM
35-36
FanconianemiacomplementationgroupQ
27
Fanconianemia,complementationgroupE
32
Fanconianemia,complementationgroupF
33
Fetalgigantism
23
FocalcorticaldysplasiaofTaylorballooncelltype
75-76
Frasiersyndrome
79-80
Fumarasedeficiency
36
Gastrointestinalstromaltumor
65-68
Gorlinsyndrome
55,73
Headandnecksquamouscellcarcinoma
Hepaticadenomas,familial
Hepatocellularcarcinoma
Hereditarybreastandovariancancer
Hereditarydiffusegastriccancer
17-18,40,56-57,74-75
39
38,44
8,10,11,12,13,16,20,46,48,51,53,57,60,72,75
15-16
Hereditaryhemorrhagictelangiectasia
70
Hereditaryleiomyomatosisandrenalcellcancer
36
Hereditarymultipleosteochondromas
28-29
Hereditaryparapanglioma-pheochromocytoma
64-68
Hirschsprungdisease
52,62
Hyperparathyroidism-jawtumorsyndrome
14
Immunodeficiency21
Intrauterinegrowthrestriction,metaphysealdysplasia,adrenal
hypoplasiacongenitaandgenitalanomalies(IMAGe)
Isolatedfamilialsomatotropinoma
38
Juvenilemyelomonocyticleukemia
49
Juvenilepolyposissyndrome
Kidneycancer
Langer-Giedionsyndrome
Li-Fraumenisyndrome
Lungcancer
Lymphangioleiomyomatosis
Lymphedema,primary,withmyelodysplasia
Lynchsyndrome
Maturity-onsetdiabetesoftheyoung,type3
17
5
10,70
20,22,36-37,40,66,77,79-80
28
19-20,74-75
6,8,17,20,22,23,25,26,27,56,60,72,74
75-76
37-38
23-24,44-47,52-53
39
83
HealthCondition
Medulloblastoma
Melanoma
Mesothelioma
Page
7,55,72,73
12,16-18,45,48,57,60,72
8-9,38,49
Mosaicvariegatedaneuploidysyndrome
13-14,19
Multipleendocrineneoplasia
42-43,62
Multiplefamilialtrichoepithelioma
21
Myelodysplasticsyndrome
38
Myhresyndrome
70
Neuroblastoma
Neurofibromatosis
6,18,50,52
46-47,49-50,53
Nijmegenbreakagesyndrome
48
Nonsyndromichearingloss
44
Nonsyndromicholoprosencephaly
55
Nonsyndromicparaganglioma
Ovariancancer
Pancreaticcancer
62,66,68,73,77-78
8,10,11,12,13,15-16,20,22,38,45-48,51,53-54,57,
59-60,72,74-75,79
8,10-12,17-18,51,72
Pancreaticcancer3
51
Perlmansyndrome
22-23
Peutz-Jegherssyndrome
Pheochromocytoma
Piebaldism
Potochi-Shaffersyndrome
Prematurechromatidseparationtrait
Primarymacronodularadrenalhyperplasia
Primaryspontaneouspneumothorax
Prostatecancer
72
42,62,65-68,73,77
41-42
29
14
7,36,43
37
10-12,15-16,20,29,48,57,78-80
Rapadilinosyndrome
61
Renalcellcarcinoma,nonpapillary
39
Renalcellcarcinoma,papillary,1
44
Renalhamartomasnephroblastomatosis
23
Retinoblastoma
60
Rhabdoidtumorpredispositionsyndrome
71
Rheumatoidarthritis
63-64
Rothmund-Thomsonsyndrome
61
Schwannomatosis
71
Shwachman-Diamondsyndrome
64
Simpson-Golabi-Behmelsyndrome
Sotossyndrome
Sporadicmacroadenomas
Stomachcancer
Thyroidcancer
Tracheoesophagealfistula
38-39
50
5
16
20,40,56,65,67
13,27,30-36,51,59,69
84
HealthCondition
Page
Trichothiodystrophy
24-27
Tuberoussclerosiscomplex
75-76
Tumorpredispositionsyndrome
Turcotsyndrome
8-9
7,44,53
Tylosiswithesophagealcancer
62
Type1diabetes
39
Uterinecancer
Uvealmelanoma
16
8-9
vonHippel-Lindausyndrome
77-78
WAGRsyndrome
79-80
Weaversyndrome
29-30
Wernersyndrome
78
Xerodermapigmentosum
24-28,80-81
XerodermapigmentosumcomplementationgroupE
21-22
XerodermapigmentosumcomplementationgroupG
27-28
XerodermapigmentosumgroupF
27
XFEprogeroidsyndrome
27
TERMS AND CONDITIONS
reveal23 is a genetic test focusing in on preventive and personalized healthcare. reveal23 identifies known genetic variants in your
saliva sample. The genetic risk profile is not diagnostic in nature and should not be used as one. Results with greater risks for certain
conditions do not necessarily mean that the patient will get that condition either now or in the future. It is important to keep in mind
that genes do not act by themselves in determining your health condition and longevity. DNA is only one of the factors that matter.
Environmental and lifestyle related factors heavily influence the outcome of many of these conditions. Thus, reveal23 assesses genetic
variations to determine what you are genetically predisposed to.
Additionally, science and knowledge in the genetic testing area change quickly, and this directory and website should not be
considered error-free or as a comprehensive source of all information on a given topic. These statements have not been evaluated by
the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.
85
References:
The material presented in this directory is entirely derived from the following resource unless otherwise referenced.
U.S. National Library of Medicine: Genetics Home Reference: https://ghr.nlm.nih.gov/
The National Library of Medicine (NLM), on the campus of the National Institutes of Health in Bethesda, Maryland, has been a center
of information innovation since its founding in 1836. The world’s largest biomedical library, NLM maintains and makes available a
vast print collection and produces electronic information resources on a wide range of topics that are searched billions of times each
year by millions of people around the globe. It also supports and conducts research, development, and training in biomedical
informatics and health information technology. In addition, the Library coordinates a 6,000-member National Network of Libraries of
Medicine that promotes and provides access to health information in communities across the United States.
Additional references where indicated:
1
National Center for Biotechnology Information (NCBI): http://www.ncbi.nlm.nih.gov/
The National Center for Biotechnology Information advances science and health by providing access to biomedical and
genomic information. Research in the NCBI Computational Biology Branch (CBB) focuses on theoretical, analytical,
and applied computational approaches to a broad range of fundamental problems in molecular biology and medicine.
The expertise of the group is concentrated in sequence analysis, protein structure/function analysis, chemical
informatics, and genome analysis. Research interests further cover a wide range of topics in computational biology and
information science. These include, but are not limited to, database searching algorithms, sequence signal identification,
mathematical models of evolution, statistical methods in virology, dynamic behavior of chemical reaction systems,
statistical text-retrieval algorithms, protein structure and function prediction, comparative genomics, taxonomic trees,
population genetics, and systems biology.
2
Universal Protein Resource (UniProt): http://www.uniprot.org/
The Universal Protein Resource (UniProt) is a comprehensive resource for protein sequence and annotation data. The
UniProt databases are the UniProt Knowledgebase (UniProtKB), the UniProt Reference Clusters (UniRef), and the
UniProt Archive (UniParc). UniProt is a collaboration between the European Bioinformatics Institute (EMBL-EBI), the
SIB Swiss Institute of Bioinformatics and the Protein Information Resource (PIR). Across the three institutes more than
100 people are involved through different tasks such as database curation, software development and support.
86
Collection Kit Instructions
87