Download Genetic Testing Diseases Caused by Single Mutations with

Genetic Testing
Diseases Caused by Single Mutations with Recessive Expression:
Sickle Cell Anemia and Cystic Fibrosis
D
As we said earlier, alterations in the order of subunits of DNA, that is, mutations, can lead to altered
proteins that may or may not work correctly. Modern molecular techniques now make detecting these
mutations relatively easy, as long as the gene responsible for a particular disorder is known. For example,
there is a gene that contains the information for making the protein hemoglobin. Recall that hemoglobin
is a protein that transports oxygen from your lungs to the rest of your body. Hemoglobin is produced in
red blood cells. As red blood cells pass through capillaries in the lungs, oxygen passes from the airways
into the capillaries, then into the red blood cells. The hemoglobin in these cells binds to oxygen in the
lungs and then delivers the oxygen to various tissues through the blood supply. The red blood cells also
pick up carbon dioxide while at those tissues and return it to the lungs where it diffuses into the airways
R
A
and is exhaled.
F
The normal gene for hemoglobin has
two of the normal allele, which is called
HbA. A certain single subunit change
or mutation on one normal allele results
in a different allele called HbS. This
allele is recessive. Recall that recessive
alleles are associated with manifestations
of the characteristic or disease only
in homozygotes. Individuals who are
homozygous for the normal HbA allele,
T
or heterozygous (HbA/HbS) do not have
sickle cell anemia. However, individuals
who are homozygous for the HbS
This illustration shows the normal, rounded shape of allele (HbS/HbS) produce an altered
human red blood cells.
hemoglobin molecule which results in
the development of sickle cell anemia.
These altered molecules are sticky. They stick to one another, producing long, rod-shaped structures in
red blood cells. These long rods of stuck-together hemoglobin cause the red blood cells to form a stiff,
elongated shape that looks like a sickle; hence the name sickle cells. These stiff cells cannot pass easily
through the tiniest blood vessels, but get trapped and clog up the circulatory system. Since the blood
cannot pass through, tissues get starved of oxygen and die, causing crises that are painful and debilitating.
87
Genetic Testing
D
Because the gene for hemoglobin is well-known, it is relatively straightforward to test someone's genes to
find out if they have the normal or abnormal alleles. If someone is homozygous for the HbS allele, that
person will have signs and symptoms of sickle cell disease early in life and won't really need a test to tell
them. But people who are heterozygous do not have the disease, but are carriers of the HbS allele. If two
individuals who are both heterozygous decide to have a child, there is a 1 in 4 chance that the child will
receive HbS alleles from both parents and will have sickle cell disease (try constructing a Punnett square
like we did earlier and calculate the types and frequencies of the possible genotypes.) If either parent is
homozygous for the normal allele, there is no chance that any child of theirs will have sickle cell disease.
Therefore, the testing and interpretation of this test is straightforward. If a person is heterozygous, they
are a carrier of the sickle cell allele and could pass it on to a child. If a person is homozygous for the
normal allele, they cannot possibly pass on a sickle cell allele to a child.
R
A
Cystic Fibrosis
F
T
Cystic fibrosis is also a genetic disease in which a mutation in a single gene leads to the disorder. Here,
the gene has the information to make a protein that is responsible for transporting salt into and out of
cells. If a mutation in the gene results in an altered protein, this transport may be disrupted. If transport is
disrupted, thick mucous can accumulate outside the cells. In the lungs, the thick mucous causes difficulty
in breathing and provides an environment in which
bacteria can grow, leading to pneumonia. In the digestive
system, the mucous prevents the secretion of digestive
enzymes, leading to digestive problems.
88
Genetic Testing
D
Unlike the case in sickle cell disease, where the same mutation is present in nearly everyone with the
disorder, a number of different mutations can lead to cystic fibrosis. Just as you could make typos in
several places while writing a paper and each one could alter the meaning of the paper, in the same way
changes in the order of subunits at several points in the gene can result in cystic fibrosis. Currently, 1415
mutations have been identified in the salt transporter gene. Some of these mutations result in severe
manifestations of cystic fibrosis while other mutations result in a milder form of the disease. Over 70%
of individuals diagnosed with cystic fibrosis have one particular mutation. Because the frequency of
the other mutations is so rare, they are not routinely tested. The inheritance pattern of cystic fibrosis is
the same as for sickle cell disease. All the mutations result in recessive alleles, so an individual must be
homozygous for mutated alleles to develop cystic fibrosis.
R
A
Without considering family history, we can look at the probability that an individual is a carrier of a
mutated allele for the salt transporter. For Caucasians of northern European descent, the overall carrier
status is 1 in 25 persons. Remember that this is an overall rate. If we lined up all Euro-Americans and
had them count off, it is not the case that every 25th person would be a carrier. The carrier rate for
individuals of other ethnic backgrounds is different. The carrier rate for African Americans is 1 in 65, for
Hispanic Americans is 1 in 46 and for Asians is 1 in 90. These numbers also lose some meaning when
one considers that individuals often are a genetic mix of ethnic backgrounds.
F
T
The tricky part of testing for cystic fibrosis is that not every possible mutation is tested for. Therefore,
a negative test does not absolutely mean that an individual is not a carrier. It just means that they are
not heterozygous for the mutated alleles that were part of the test. They may in fact be heterozygous for
another mutated allele. Therefore, following a negative test, an individual’s chance of being a carrier is not,
as is the case in sickle cell disease, zero. For Euro¬Americans the chance of being a carrier drops from 1
in 25 to 1 in 140, a far lower number, but clearly nowhere near zero. Following testing, the carrier rates
for African Americans drops to 1 in 207, for Hispanic Americans to 1 in 105 and is currently unknown
for Asians because of insufficient research into the frequency of particular alleles in that population.
Such statistics might be helpful in identifying higher risk groups, but also represent a false sense of
genetic homogeneity across ethnic groups.
89
Genetic Testing
Autosomal Dominant, Genetically-linked Disease: Huntington’s Disease
Genetic testing for Huntington disease is different from sickle cell disease and cystic fibrosis for two
reasons. First, the mutated allele that results in Huntington disease is dominant. That is, a person who
is heterozygous is not just a carrier, but will in fact develop Huntington’s disease. Also, unlike sickle cell
disease and cystic fibrosis where persons homozygous for the mutated alleles do not need testing because
the disease becomes apparent at or soon after birth, Huntington’s disease does not typically develop until
mid-life (around age 40 or a little later). Individuals who may be only carriers of the sickle cell or cystic
fibrosis alleles can be tested to find out if they could transmit the disease to their children, even though
they themselves are unaffected. But healthy individuals who test positive for the Huntington disease allele
receive the knowledge that they themselves will develop a deadly, progressive disease sometime later in life.
Also, unlike recessive disorders, where a child can get the disease only if both parents are carriers, a person
who tests positive for one
Huntington’s
disease
allele not only will likely
develop the disease but
also has a 50% chance
of passing on that allele
(and
therefore
the
disease) to any child,
regardless of the genotype
of the other parent.
90
Genetic Testing
Genetically Inherited
Increased Risk of Cancer
D
The majority of genetic tests currently available
are for single gene disorders like sickle cell disease,
cystic fibrosis and Huntington disease. However,
the majority of disorders associated with genetic
changes are not the result of a mutation in a single
gene. Multiple genes may be involved, or genes
may interact with the environment to produce a
Mutations occur all the time. Right this minute, you
are accumulating mutations in your DNA. Most of
the mutations will occur in parts of the DNA that
don't contain genes, or will be mutations that don't
result in a non-functional protein. But sometimes
a mutation will occur that matters. If only one of
your BRCA1 alleles gets mutated, you're fine. But
if lightning strikes twice and the second allele is
also mutated, that cell may become cancerous.
Such mutations are called somatic mutations. This
means that only you will be affected. You won't
pass this mutation on to your children.
R
particular phenotype. Testing for these types of
disorders such as cancer, diabetes, heart disease,
Alzheimer’s disease, and others is much more
complex and does not provide the precise answers But what if the mutation in the BRCA1 gene occurs
obtained when testing for a single gene disorder.
in a cell that is developing into an egg or sperm?
This is called a germ-line mutation. A child that
Let's use cancer as an example. The development resulted from such an egg or sperm would have one
of cancer is a complex process, but the first step is mutated BRCA1 allele in every cell of her body.
usually a mutation in one of only a few genes. An It's as though every cell in her body had been hit by
example of one of these genes is the BRCA1 gene. lightning once. Now, during the life of that person,
This gene produces a protein that is involved in the any cell that gets just one more BRCA1 mutation
regulation of cell division. Cancer develops when may develop into cancer, particularly breast or
cells begin dividing uncontrollably. This can occur ovarian cancers. Additionally, that person has a
if one or more mutations have resulted in a failure 50% chance of passing the initial inherited mutated
to stop cells from dividing. Certain mutations in allele along to any of her children. A person who
the BRCA1 gene result in a non-functional protein inherits one mutated BRCA1 allele in every cell
that fails to regulate cell division. These mutations has an inherited susceptibility to cancer. There is
are recessive. As long as a person has one normal no guarantee that they will develop cancer, but the
BRCA1 gene, regulation of cell division will be chances are much greater than for someone who
normal. However, if a cell contains two mutated inherited no mutated alleles to begin with. Genetic
copies, that cell will begin to divide out of control testing in this case can only provide a probability
and may develop into a tumor.
that an individual will develop cancer.
A
F
T
91
Genetic Testing
DNA Outside the Nucleus: Mitochondrial DNA and Diseases Linked to It
Although almost all DNA resides in the nucleus of cells, cells also have small, distinct structures called
organelles, each type of which has its own function. Within one of these organelles, the mitochondria,
there is a very small amount of additional genetic material containing DNA. Mitochondria serve as
energy-producing components of the cell. Because mitochondria are in the cytoplasm and not in the
nucleus, their genetic material is passed on through the mother’s genetic line because the egg carries
nearly all of the cytoplasm that is contained in the zygote, which is the cell produced by the union of
a sperm and egg at conception. Scientists have only recently begun to understand the importance of
this mitochondrial genetic material. It now seems that over 40 distinct health disorders have been
associated with mutations of this genetic material. One or more organs may be affected and symptoms
vary among disorders and among patients with specific disorders. Symptoms that may occur include
muscle weakness and lack of coordination, visual or hearing problems, nerve problems, mental disorders,
and diabetes (for more information, see http://my.clevelandclinic.org/disorders/Mitochondrial_Disease/
hic_Myths_and_Facts_About_Mitochondrial_Diseases.aspx)
92