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ΒΙΟΧΗΜΙΚΗ ΓΕΝΕΤΙΚΗ
Kεφάλαιο 7
Λάρισα, 2007
7.1. Major pathway of phenylalanine metabolism. Different enzymatic
defects in this pathway cause (1) classical PKU, (2) tyrosinasenegative oculocutaneous albinism, (3) AKU, and (4) tyrosinemias.
Table 7-1. Disorders of Metabolism (Ι)
Name
Prevalence
Chromosomal
location
Mutant gene product
Carbohydrate Disorders
Classical galactosemia
1/35,000
1/60,000
to
Galactose-1-phosphate
transferase
uridyl
Hereditary fructose intolerance
1/20,000
Fructose
aldolase
Fructosuria
∼1/100,000
Fructokinase
2p23
Hypolactasia (adult)
Common
Lactase
2q21
Diabetes mellitus type 1
1/400
(Caucasians)
Unknown
Polygenic
Diabetes mellitus type 2
1/20
Unknown
Polygenic
Maturity-onset diabetes of youth
(MODY)
∼1/400
Glucokinase (60%)
7p13
1,6-bisphosphate
9p13
9q13-q32
Table 7-1. Disorders of Metabolism (II)
Name
Prevalence
Mutant gene product
Chromosomal location
Phenylketonuria
1/10,000
Phenylalanine hydroxylase
12q24
Tyrosinemia (type 1)
1/100,000
Fumarylacetoacetate hydrolase
15q23-25
Maple syrup urine disease
1/180,000
Branched-chain α-ketoacid dehydrogenase
(multiple subunits)
Multiple loci
Alkaptonuria
1/250,000
Homogentisic acid oxidase
3q2
Homocystinuria
1/340,000
Cystathionine β-synthase
21q2
Oculocutaneous albinism
1/35,000
Tyrosinase
11q
Cystinosis
1/100,000
CTNS
17p13
Cystinuria
1/7,000
SLC3A1 (type 1)
2p
SLC7A9 (types II & III)
19q13
Amino Acid Disorders
Lipid Disorders
MCAD
1/20,000
Medium-chain acyl-CoA dehydrogenase
1p31
LCAD
Rare
Long-chain acyl-CoA dehydrogenase
2q34-q35
SLO
1/10,000
Δ7-sterol reductase
11q12-q13
Methylmalonic acidemia
1/20,000
Methylmalonyl-CoA mutase
6p
Propionic acidemia
Rare
Propionyl-CoA carboxylase
13q32; 3q
Organic Acid Disorders
Table 7-1. Disorders of Metabolism (III)
Name
Prevalence
Mutant gene product
Chromosomal
location
Urea Cycle Defects
Ornithine transcarbamylase
deficiency
1/70,000 to
1/100,000
Ornithine carbamyl transferase
Xp21
Carbamyl phosphate synthetase
deficiency
1/70,000 to
1/100,000
Carbamyl phosphate
synthetase I
2p
Argininosuccinic acid synthetase
deficiency
1/70,000 to
1/100,000
Argininosuccinic acid
synthetase
9q34
Cytochrome C oxidase deficiency
Rare
Cytochrome oxidase peptides
Multiple loci
Pyruvate carboxylase deficiency
Rare
Pyruvate carboxylase
11q
Pyruvate dehydrogenase complex
(E1) deficiency
Rare
Pyruvate decarboxylase, E1α
Xp22
NADH-CoQ reductase deficiency
Rare
Multiple nuclear genes
Multiple loci
Wilson disease
1/50,000
ATP7B
13q14
Menkes disease
1/250,000
ATP7A
Xq13
Hemochromatosis
1/200 to 1/500
(European)
HFE
6p21
Acrodermatitis enteropathica
Rare
SLC39A4
8q24
Energy Production Defects
Heavy Metal Transport Defects
7.2 Major pathways of galactose metabolism. The most common enzymatic abnormality
producing galactosemia is a defect of GAL-1-P uridyl transferase. Defects of galactokinase
or of UDP-galactose 4-epimerase are much less common causes of galactosemia.
7.3 Summary of glucose, fructose, and glycogen metabolism. Enzymatic defects in this pathway
cause (1) hyperglycemia, (2) Von Gierke disease, (3) fructosuria, (4) hereditary fructose
intolerance, (5) Cori disease, (6) Anderson disease, (7) Tarui disease, and (8) FBPase deficiency.
Table 7-2. Glycogen Storage Disorders
Type
Defect
Major affected tissues
Ia (Von Gierke)
Glucose-6-phosphatase
Liver, kidney, intestine
Ib
Microsomal glucose-6phosphate transport
Liver, kidney, intestine, neutrophils
II (Pompe)
Lysosomal acid αglucosidase
Muscle, heart
IIIa (Cori)
Glycogen debranching
enzyme
Liver, muscle
IIIb
Glycogen debranching
enzyme
Liver
IV (Anderson)
Branching enzyme
Liver, muscle
V (McArdle)
Muscle phosphorylase
Muscle
VI (Hers)
Liver phosphorylase
Liver
VII (Tarui)
Muscle phosphofructokinase
Muscle
Table 7-3. Phenylalanine Content of Some Common Foods
Food
Measure
Phenylalanine (mg)
Turkey, light meat
1 cup
1662
Tuna, water-packed
1 cup
1534
Baked beans
1 cup
726
Lowfat milk, 2%
1 cup
393
Soy milk
1 ounce
46
Breast milk
1 ounce
14
Broccoli (raw)
3 tablespoons
28
Potato (baked)
2 tablespoons
14
Watermelon
½ cup
12
Grapefruit (fresh)
¼ fruit
13
Beer
6 ounces
11
Gelatin dessert
½ cup
36
7.4 Sources of calories of individuals with PKU at different ages. The amount of no-protein
medical foods and low-protein medical foods eaten increases with age as the need for
energy and protein increases. (Courtesy Kathleen Huntington and Diane Waggoner,
University of Oregon Health Sciences.)
7.5 Summary of fatty acid
metabolism: (1) fatty acid
entry into a cell,
(2)
activation
and
transesterification,
(3) mitochondrial uptake,
(4) oxidation via β-oxidation,
and (5) formation of ketone
bodies. Note that mediumchain
fatty
acids
can
traverse the mitochondrial
membrane without carnitinemediated transport.
7.6 A child with Smith-Lemli-Opitz
syndrome. Note the broad nasal root,
upturned nasal tip, and inner
epicanthal folds that are characteristic
of this disorder. (Nowaczyk MJ,
Whelan DT, Hill RE [1998] Smith-LemliOpitz syndrome: phenotypic extreme
with minimal findings. Am J Med
Genet 78:419-423.)
Table 7-4. Mucopolysaccharidoses*
Name
Mutant enzyme
Clinical features
Hurler/Scheie
α-1-Iduronidase
Coarse face, hepatosplenomegaly, corneal clouding,
dysostosis multiplex,† mental retardation
Hunter
Iduronate sulfatase
Coarse face, hepatosplenomegaly, dysostosis multiplex,
mental retardation, behavioral problems
Sanfilippo A
Heparan-N-sulfamidase
Behavioral problems, dysostosis multiplex, mental
retardation
Sanfilippo B
α-N-Acetylglucosaminidase
Behavioral problems, dysostosis multiplex, mental
retardation
Sanfilippo C
Acetyl-CoA: α-glucosaminide Nacetyltransferase
Behavioral problems, dysostosis multiplex, mental
retardation
Sanfilippo D
N-Acetylglucosamine-6-sulfatase
Behavioral problems, dysostosis multiplex, mental
retardation
Morquio A
N-Acetylglucosamine-6-sulfatase
Short stature, bony dysplasia, hearing loss
Morquio B
β-Galactosidase
Short stature, bony dysplasia, hearing loss
Maroteaux-Lamy
Aryl sulfatase B
Short stature, corneal clouding, cardiac valvular disease,
dysostosis multiplex
Sly
β-Glucuronidase
Coarse face, hepatosplenomegaly, corneal clouding,
dysostosis multiplex
*Hunter
syndrome
is
an
X-linked
recessive
disorder;
the
remaining
MPS
disorders
are
autosomal
recessive.
†Dysostosis multiplex is a distinctive pattern of bony changes including a thickened skull, anterior thickening of the ribs, vertebral abnormalities, and
shortened and thickened long bones.
7.7 A, A boy with a mutation in α-liduronidase,
which
causes
Hurler
syndrome. Note his coarse facial features,
crouched stance, thickened digits, and
protuberant abdomen. B, Transgenic mice
with a targeted disruption of α-liduronidase. Progressive coarsening of
the face is apparent as 8-week-old mice
(left) grow to become 52-week-old mice
(right). (Courtesy Dr. Lorne Clarke,
University of British Columbia.)
Table 7-5. Lysosomal Storage Disorders*
Name
Mutant enzyme
Clinical features
Tay-Sachs
β-Hexosaminidase (A
isoenzyme)
Hypotonia, spasticity, seizures, blindness
Gaucher (type 1; nonneuropathic)
β-Glucosidase
Splenomegaly, hepatomegaly, bone marrow
infiltration, brain usually spared
Niemann-Pick, type 1A
Sphingomyelinase
Hepatomegaly, corneal opacities, brain deterioration
Fabry
α-Galactosidase
Paresthesia of the hands and feet, corneal dystrophy,
hypertension, renal failure, cardiomyopathy
GM1 gangliosidosis
(infantile)
β-Galactosidase
Organomegaly, dysostosis multiplex,† cardiac failure
Krabbe
β-Galactosidase
Hypertonicity, blindness, deafness, seizures,
(galactosylceramide-specific) atrophy of the brain
Metachromatic
leukodystrophy
Aryl sulfatase A
Ataxia, weakness, blindness, brain atrophy (lateinfantile)
Sandhoff
β-Hexosaminidase (total)
Optic atrophy, spasticity, seizures
Schindler
α-N-Acetylgalactosaminidase
Seizures, optic atrophy, retardation
Multiple sulfatase
deficiency
Aryl sulfatase A, B, C
Retardation, coarse facial features, weakness,
hepatosplenomegaly, dysostosis multiplex
*Of the lysosomal storage disorders included in this table, Fabry syndrome is X-linked recessive and the remainder are autosomal recessive.
†Dysostosis multiplex is a distinctive pattern of bony changes including a thickened skull, anterior thickening of the ribs, vertebral abnormalities, and
shortened and thickened long bones.
7.8 Schematic diagram of the urea cycle. AS, Argininosuccinase; ASA, argininosuccinic acid
synthetase; CPS, carbamyl phosphate synthetase; NAGS, N-acetylglutamate synthetase;
OTC, ornithine transcarbamylase.
5.18 The circular mitochondrial
DNA genome. Locations of
protein-encoding
genes
(for
reduced nicotinamide adenine
dinucleotide
[NADH]
dehydrogenase, cytochrome c
oxidase,
cytochrome
c
oxidoreductase,
and
ATP
synthase) are shown, as are the
locations of the two ribosomal
RNA genes and 22 transfer RNA
genes (designated by single
letters). The replication origins of
the heavy (OH) and light (OL)
chains and the noncoding D loop
(also known as the control
region) are shown. (Modified
from
Wallace
DC
[1992]
Mitochondrial
genetics:
a
paradigm
for
aging
and
degenerative diseases? Science
256:628-632.)
7.9 Comparison of hemosiderin stain of normal liver (upper left) with hemosiderin stain of
livers from individuals affected with hemochromatosis (upper right, lower right, and lower
left). Note the varying degree of increased deposition of hemosiderin livers of HH
homozygotes. This damages the liver, impairs its function, and can lead to cirrhosis and liver
cancer.
2.1 The anatomy of the cell.
7.10 A child with acrodermatitis
enteropathica
caused
by
mutations in SLC39A4, encoding
a protein necessary for intestinal
absorption of zinc. The resulting
deficiency of zinc produces a
characteristic scaly, red rash
around the mouth, genitals,
buttocks, and limbs. (Courtesy
Dr. Virginia Sybert, University of
Washington.)
Table 7-6. Examples of Effects of Gene Polymorphisms on Drug Response
Gene
Enzyme/Target
Drug
Clinical response
CYP2
D6
Cytochrome P450 2D6
Codeine
Individuals homozygous for an inactivating mutation do not
metabolize codeine to morphine and thus experience no
analgesic effect
CYP2
C9
Cytochrome P450 2C9
Warfarin
Individuals heterozygous for a polymorphism need a lower
dose of warfarin to maintain anticoagulation
NAT2
N-Acetyl transferase 2
Isoniazid
Individuals homozygous for "slow-acetylation"
polymorphisms are more susceptible to isoniazid toxicity
TPMT
Thiopurine Smethyltransferase
Azathioprine
Individuals homozygous for an inactivating mutation
develop severe toxicity if treated with standard doses of
azathioprine
ADRB
2
β-Adrenergic receptor
Albuterol
Individuals homozygous for a polymorphism get worse
with regular use of albuterol
KCNE
2
Potassium channel,
voltage-gated
Clarithromycin
Individuals heterozygous for a polymorphism are more
susceptible to life-threatening arrhythmias
SUR1
Sulfonylurea receptor 1
Sulfonylureas
Individuals heterozygous for polymorphisms exhibit
diminished sensitivity to sulfonylurea-stimulated insulin
secretion
F5
Coagulation factor V
(Leiden)
Oral
contraceptives
Individuals heterozygous for a polymorphism are at
increased risk for venous thrombosis
7.11 Different combinations of single nucleotide polymorphisms (SNPs) are found in different
individuals. The locations of these SNPs can be pinpointed on maps of human genes.
Subsequently, they can be used to create profiles that are associated with differences in response
to a drug, such as efficacy and nonefficacy. (Adapted from Roses A [2000] Pharmacogenetics and
the practice of medicine. Nature 405:857-865.)
Αρχές Ιατρικής
Γενετικής
Kεφάλαιο 8
Λάρισα, 2007
8.1 The number of coding genes
mapped
to
specific
chromosome locations. As of
March 2003, the number of
genes identified is just over
14,000. (From Guyer MS, Collins
FS [1995] How is the Human
Genome Project doing, and
what have we learned so far?
Proc Natl Acad Sci U S A
92:10841-10848;
the
Online
Genome Data Base and the
Ensembl data base, April, 2005.
8.2 Loci A and B are linked on the same chromosome, so alleles A1 and B1 are usually inherited together.
Locus C is on a different chromosome, so it is not linked to A and B, and its alleles are transmitted
independently of the alleles of A and B.
8.3A The genetic results of crossover. A, No crossover: A1 and B1 remain together after meiosis. B, A
crossover between A and B results in a recombination: A1 and B2 are inherited together on one
chromosome, and A2 and B1 are inherited together on another chromosome. C, A double crossover between
A and B results in no recombination of alleles. (Modified from McCance KL, Huether SE [1998]
Pathophysiology, 3rd ed. Mosby, St Louis.)
8.4 Crossover is more likely between loci that
are far apart on chromosomes (left) than
between those that are close together (right).
8.5 A, An NF1 pedigree in which each member has been typed for the 1F10 polymorphism. Genotypes for this twoallele marker locus are shown below each individual in the pedigree. Affected pedigree members are indicated by a
shaded symbol. B, An autoradiogram for the 1F10 polymorphism in this family.
8.6 An NF1 pedigree in which each member has been typed for the 1F10 polymorphism. The
marker genotypes are shown below each individual in the pedigree.
8.7 The LOD score (y axis) is plotted against the recombination frequency (x axis) to determine the most likely
recombination frequency for a pair of loci.
8.8 A genetic map of chromosome 9,
showing the locations of a large number of
polymorphic
markers.
Because
recombination rates are usually higher in
female meiosis, the distances between
markers (in centiMorgans) are larger for
females than for males. (From Attwood J,
Chiano M, Collins A, et al. [1994] CEPH
consortium Map of chromosome 9.
Genomics 19:203-214.)
8.9 An autosomal dominant disease gene is segregating in this family. A, A closely linked two-allele RFLP has
been typed for each member of the family, but linkage phase cannot be determined (uninformative mating). B, A
closely linked six-allele STRP has been typed for each family member, and linkage phase can now be determined
(informative mating).
8.10 A family in which markers A, B, C, D,
and E have been typed and assessed for
linkage with an autosomal dominant
disease-causing mutation. As explained
in the text, recombination is seen
between the disease locus and marker A
in individual III-2 and between the disease
locus and marker D in individual III-5.
8.11 A fundus photograph illustrating clumps of pigment deposits and retinal blood vessel attenuation in
retinitis pigmentosa. (Courtesy Dr. Don Creel, University of Utah Health Sciences Center.)
8.12 Linkage disequilibrium between
the myotonic dystrophy (DM) locus
and two linked loci, A and B. The DM
mutation first arises on the
chromosome
with
the
A1B2
haplotype. After a number of
generations have passed, most
chromosomes carrying the DM
mutation still have the A1B2
haplotype, but, as a result of
recombination, the DM mutation is
also found on other haplotypes.
Because the A1B2 haplotype is seen
in 70% of DM chromosomes but only
25% of normal chromosomes, there
is linkage disequilibrium between
DM and loci A and B. Because locus
B is closer to DM, it has greater
linkage disequilibrium with DM than
does locus A.
8.13 Ankylosing spondylitis, caused by
ossification of discs, joints, and ligaments in the
spinal column. Note the characteristic posture.
(Modified from Mourad LA [1991] Orthopedic
Disorders. Mosby, St Louis.)
Table 8-1. Association of Ankylosing Spondylitis and the HLA-B27 Allele in a
Hypothetical Population*
Ankylosing spondylitis
HLA-B27
Present
Absent
Present
90
1,000
Absent
10
9,000
*This table shows that individuals with ankylosing spondylitis are much more likely to have the HLA-B27 allele than are
normal controls.
8.14 Localization of a disease gene through deletion
mapping. A series of overlapping deletions is studied in
which each deletion produces the disease phenotype.
The region of overlap of all deletions defines the
approximate location of the disease gene.
8.15 Mapping a DNA segment to a chromosome location through in situ hybridization.
8.16 Gene mapping by somatic cell
hybridization. The human and
rodent cells that fused are selected
with the use of a medium such as
HAT. The hybrid cells preferentially
lose
human
chromosomes,
resulting in clones that each have
only a few human chromosomes.
Each clone is examined to
determine whether the gene is
present, thus assigning the gene
to a specific chromosome.
8.17 A Southern blot used in a somatic cell hybridization gene mapping experiment (compare with panel shown in
Table 8-2). Human and mouse bands differ in size because the two species have different recognition sequences.
The human gene probe hybridizes only to the hybrid cells 1, 3, 4, and 7, showing that the probe hybridizes only
when chromosome 9 is present (see Table 8-2).
Table 8-2. Somatic Cell Hybridization Panel*
Clone
DNA
segment
1
2 3
4
5 6 7 8 9
10
11
12
13
14
15
16
17
18
19
20
21
22
X
Y
1
+
-
-
-
+
-
+ + + +
-
+
+
-
-
+
-
+
-
+
-
-
-
+
-
2
-
+
+ +
-
+
-
-
+
-
-
-
+
+
+
-
-
+
+
+
+
-
-
3
+
-
-
-
-
+ + + + +
-
-
-
+
-
+
-
+
-
+
+
-
+
-
-
4
+
+
-
+
-
-
-
+
-
+
-
+
+
-
-
-
+
-
+
-
-
+
-
-
-
5
-
-
+ +
+
+ +
-
-
-
+
-
-
+
-
+
-
+
-
-
+
+
-
+
+
6
-
+
-
+
-
-
+
-
-
-
+
+
-
+
+
-
+
-
+
-
-
-
+
+
-
7
+
-
+
-
+
-
+ + + +
-
+
-
-
-
+
+
-
+
-
+
+
-
+
-
8
-
-
+ +
+
-
-
+
+
+
-
+
-
+
+
-
+
+
-
-
-
-
+
+
-
-
-
*Note that the DNA segment being tested shows a positive hybridization signal to clones 1, 3, 4, and 7. Each of these clones contains
chromosome 9, whereas clones 2, 5, 6, and 8 do not contain this chromosome. This pattern localizes the DNA segment to chromosome 9.
8.18 Radiation hybrid mapping. A cell
line containing a human chromosome is
irradiated to produce chromosome
breaks.
The
resulting
human
chromosome fragments are fused with
rodent chromosomes so that they will
survive. The presence of human
chromosome material in rodent cells can
be detected by the presence of Alu
sequences. Closely linked loci, such as
A and B, are frequently found on the
same chromosome fragment, whereas
loosely linked loci, such as A and C, are
infrequently found on the same
chromosome fragment.
8.19 The creation of human DNA libraries. Left, A total genomic library is created using a partial restriction digest
of human DNA and then cloning the fragments into vectors such as phage, cosmids, or YACs. Right, A cDNA
library is created by purifying mRNA from a tissue and exposing it to reverse transcriptase to create cDNA
sequences, which are then cloned into vectors.
8.20 A probe was tested against eight clones taken from a human YAC library. The probe hybridized with two of
the clones (lanes 6 and 7), indicating overlap between the DNA in the probe and the DNA in each of the two YAC
clones.
8.21 The use of STSs to indicate overlap between DNA segments in establishing a contig map. Overlap is indicated
when PCR primers for a specific STS amplify DNA from different DNA segments taken from a genomic library.
8.22 An example of a YAC contig map on chromosome 5 in the region of the adenomatous polyposis coli (APC) gene.
8.23 The exon trapping technique. The
human DNA segment is placed in a
plasmid vector using recombinant DNA
techniques. The plasmid vector is
cloned into a yeast or mammalian cell
that contains appropriate transcriptional
machinery. Mature mRNA is isolated and
converted to cDNA. The cDNA sequence
can then be amplified with PCR to
determine its length. If the human DNA
segment contains an exon or exons, the
resulting fragment will be longer than if
it does not.
8.24 An example of a Northern
blot, showing the hybridization
of a cDNA probe from the
EVI2A gene (a gene embedded
within an intron of the NF1
gene) with mRNA from adrenal
gland, brain, and fibroblasts.
This result indicates that EVI2A
is expressed in the brain at a
much higher level than in the
other two tissues. (Courtesy
Dr.
Richard
Cawthon,
University of Utah Health
Sciences Center.)
Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (I)
Disease
Chromosome
location
Gene product
α-1-Antitrypsin deficiency
14q
Serine protease inhibitor
α-Thalassemia
16p
α-Globin component of hemoglobin
β-Thalassemia
11p
β-Globin component of hemoglobin
Achondroplasia
4p
Fibroblast growth factor receptor 3
Polycystic kidney disease
16p
Polycystin-1 membrane protein
4p
Polycystin-2 membrane protein
6p
Fibrocystin-possible receptor protein
(type 1)
11q
Tyrosinase
(type 2)
15q
Tyrosine transporter
Alzheimer disease*
14q
Presenilin 1
1q
Presenilin 2
19q
Apolipoprotein E
21q
β-Amyloid precursor protein
Amyotrophic lateral sclerosis
21q
Superoxide dismutase 1
Angelman syndrome
15q
Ubiquitin-protein ligase E3A
Ataxia telangiectasia
11q
Cell cycle control protein
Beckwith-Wiedemann syndrome
11p
Insulin-like growth factor II
Bloom syndrome
15q
RecQ helicase
Breast cancer (familial)
17q
BRCA1 tumor suppressor/DNA repair protein
Albinism, oculocutaneous
Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (II)
Li-Fraumeni syndrome
13q
BRCA2 tumor suppressor/DNA repair protein
22q
CHEK2 DNA repair protein
17p
P53 tumor suppressor
22q
CHEK2 DNA repair protein
Charcot-Marie-Tooth disease (at least 17 loci now identified)
(type 1A)*
17p
Peripheral myelin protein 22
(type 1B)
1q
Myelin protein zero
(type 2A1)
1p
KIF1B motor protein
(type 2B1)
1q
Lamin A/C nuclear envelope protein
(type 4A)
8q
Ganglioside-induced differentiation-associated protein-1
(type 4B1)
11q
Myotubularin-related protein-2
(type X1)
Xq
Connexin-32 gap junction protein
Cystic fibrosis
7q
Cystic fibrosis transmembrane regulator (CFTR)
Deafness, nonsyndromic (more than 75
genes identified to date;
representative examples shown
here)
13q
5q
7q
Connexin-26 gap junction protein
Actin polymerization regulator
Pendrin (anion transporter; mutations also found in Pendred
syndrome)
11q
α-Tectorin
(MODY1)
20q
Hepatocyte nuclear factor-4α
(MODY2)
7p
Glucokinase
(MODY3)
12q
Hepatocyte nuclear factor-1α
(MODY4)
13q
Insulin promoter factor-1
(MODY5)
17q
Hepatic transcription factor-2
(MODY6)
2q
NeuroD transcription factor
Diabetes
Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (III)
Duchenne/Becker muscular dystrophy
Xp
Dystrophin
Ehlers-Danlos syndrome*
2q
Collagen (COL3A1); there are numerous types of this disorder, most of
which are produced by mutations in collagen genes
Ellis van Creveld syndrome
4p
Protein with possible leucine zipper domain
Familial polyposis coli
5q
APC tumor suppressor
Fragile X syndrome
Xq
FMR1 RNA-binding protein
Friedreich ataxia
9q
Frataxin mitochondrial protein
Galactosemia
9p
Galactose-1-phosphate-uridyltransferase
Hemochromatosis (adult)
6p
Transferrin receptor binding protein
Hemophilia A
Xq
Clotting factor VIII
Hemophilia B
Xq
Clotting factor IX
Hereditary nonpolyposis colorectal cancer
3p
2p
MLH1 DNA mismatch repair protein
MSH2 DNA mismatch repair protein
2q
PMS1 DNA mismatch repair protein
7p
PMS2 DNA mismatch repair protein
2p
MSH6 DNA mismatch repair protein
14q
MLH3 DNA mismatch repair protein
(type 1)*
10q
RET tyrosine kinase proto-oncogene
(type 2)
13q
Endothelin receptor type B
Huntington disease
4p
Huntingtin
Hypercholesterolemia (familial)
19p
LDL receptor
Hirschsprung disease
Long QT syndrome
Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (IV)
(LQT1)*
11p
KVLQT1 cardiac potassium channel α subunit
(LQT2)
7q
HERG cardiac potassium channel
(LQT3)
3p
SCN5A cardiac sodium channel
(LQT5)
21q
KCNE1 cardiac potassium channel β subunit
(LQT6)
21q
KCNE2 cardiac potassium channel
Marfan syndrome type 1
15q
Fibrillin-1
Marfan syndrome type 2
3p
TGF-beta receptor 2
Melanoma (familial)*
9p
Cyclin-dependent kinase inhibitor tumor suppressor
12q
Cyclin-dependent kinase 4
19q
Protein kinase
3q
Zinc finger protein
Myoclonus epilepsy (UnverrichtLundborg)
21q
Cystatin B cysteine protease inhibitor
Neurofibromatosis type 1
17q
Neurofibromin tumor suppressor
Neurofibromatosis type 2
22q
Merlin (schwannomin) tumor suppressor
(familial)
4q
α-Synuclein
(autosomal recessive early-onset)
6q
Parkin
Phenylketonuria
12q
Phenylalanine hydroxylase
Myotonic dystrophy
Parkinson disease
Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (V)
Retinitis pigmentosa* (more than 20
genes cloned to date; representative
examples shown here)
3q
6p
11q
Rhodopsin
TULP1 tubby-like protein
Rod outer segment membrane protein-1
6p
Peripherin/RDS
4p
Retinal rod photoreceptor cGMP phosphodiesterase, β subunit
Xp
Retinitis pigmentosa GTPase regulator
4p
Retinal rod cGMP-gated channel, α subunit
Retinoblastoma
13q
pRB tumor suppressor
Rett syndrome
Xq
Methyl CpG binding protein
Sickle cell disease
11p
β-Globin component of hemoglobin
Smith-Lemli-Opitz syndrome
11q
7-Dehydrocholesterol reductase
Stargardt disease
1p
ATP-binding cassette transporter
Tay-Sachs disease
15q
Hexosaminidase A
(type 1)*
9q
Hamartin tumor suppressor
(type 2)
16p
Tuberin tumor suppressor
(type 1B)
11q
Myosin VIIA
(type 1C)
11p
Harmonin (PDZ domain-containing protein)
(type 1D)
10q
Cadherin-23
(type 1F)
10q
Protocadherin-15
(type 2A)
1q
Usherin (extracellular matrix protein)
(type 3A)
3q
Predicted transmembrane protein
Tuberous sclerosis
Usher syndrome*
Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (VI)
Waardenburg syndrome
(type 1 and 3)*
2q
PAX3 transcription factor
(type 2A)
3p
MITF transcription factor
(type 2D)
8q
SNAI2 transcription factor
(type 4)
13q
Endothelin B receptor
(type 4)
20q
Endothelin 3
(type 4)
22q
SOX10 transcription factor
Wilms tumor*
11p
WT1 zinc finger protein tumor suppressor
Wilson disease
13q
Copper transporting ATPase
von Willebrand disease
12q
von Willebrand clotting factor
*Additional disease-causing loci have been mapped and/or cloned.