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45
Uniparental Disomy and
Repeat Mutations
Occurs when both copies of a chromosome are inherited from the same parent. If one copy is an
identical copy of one homolog of a chromosome from a parent, then this is called
isodisomy.
If
the parent passes on both homologs of a chromosome, then this is termed
heterodisomy.
In
both cases, the child does not receive a copy of that chromosome from the other parent.
A. Causes.
1.
UPD can be caused by the loss of one chromosome from a cell where there is a trisomy for
that particular chromosome (“
trisomy rescue
”).
2.
UPD can also be caused when a gamete with two copies of a chromosome combines with
a gamete with no copies of that chromosome.
B. Disorders.
UPD can be a causative factor in a number of disorders as indicated below.
1. Prader-Willi and Angelman (PW/A) syndromes.
a.
Because these syndromes are mostly due to a microdeletion on chromosome 15, they
are discussed in Chapter 11. However, UPD can cause the syndromes because the
involved region is under control of genomic imprinting. Genomic imprinting is where
the expression of a gene or genes depends on the parent of origin.
b.
If the PW/A region is deleted on the paternal chromosome 15, then Prader-Willi syn-
drome occurs. UPD for the maternal chromosome 15 is effectively a deletion of the
paternal PW/A region so that Prader-Willi syndrome occurs.
c.
If the PW/A region is deleted on the maternal chromosome 15, then Angelman syn-
drome occurs. UPD for paternal chromosome 15 is effectively a deletion of the mater-
nal PW/A region so that Angelman syndrome occurs.
2. Beckwith-Wiedemann syndrome (BWS).
BWS can be caused by UPD where there is an
excess of paternal material or loss of maternal material at chromosome 11p15. See
Chapter 1-IV for more information on BWS.
3. Autosomal recessive disorders.
In some cases, autosomal recessive disorders can be
caused by UPD. Although this is a rare occurrence, UPD should be considered when only
one parent is a carrier. For example, CF is an autosomal recessive disease, so both copies
of the allele must have a mutation for the disease to be manifested. In UPD cases, the chil-
dren have CF because they received the two mutations from the same parent.
II. UNSTABLE EXPANDING REPEAT MUTATIONS
A.
Dynamic mutations are mutations that involve the
expansion of a repeat sequence
either out-
side or inside the gene.
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B.
Dynamic mutations represent a new class of mutation in humans for which there is no coun-
terpart in other organisms. The exact mechanism by which dynamic mutations occurs is not
known.
C.
Although dynamic mutations may occur during mitosis resulting in mosaicism, dynamic
mutations often occur only during meiosis producing the female or male gametes.
D. Threshold Length.
Dynamic mutations demonstrate a
threshold length. Below a certain thresh-
old length,
the repeat sequence is stable, does not cause disease, and is propagated to succes-
sive generations without change in length.
Above a certain threshold length,
the repeat sequence
is unstable, causes disease, and is propagated to successive generations in expanding lengths.
E. Anticipation.
Dynamic mutations demonstrate anticipation. Anticipation is one of the hall-
marks of diseases caused by dynamic mutations. Anticipation means that a genetic disorder
displays an
earlier age of onset
and/or a
greater degree of severity
in successive generations of
the family pedigree.
F. Premutation Status.
A normal person may have certain number of repeats that have a high
likelihood of being expanded during meiosis (i.e., a permutation status) such that his off-
spring are at increased risk of inheriting the disease.
G.
Most of dynamic mutation diseases are caused by expansion of trinucleotide repeats,
although longer repeats do play a role in some diseases. Dynamic mutations are divided into
two categories: highly expanded repeats outside the gene and moderately expanded CAG
repeats inside the gene.
III. HIGHLY EXPANDED REPEATS OUTSIDE THE GENE
In this category of dynamic mutation, various repeat sequences (e.g., CGG, CCG, GAA, CTG,
CCTG, ATTCT, or CCCCGCCCCGCG) undergo very large expansions. Below threshold length,
expansions are
5 to 50 repeats. Above threshold length, expansions are 100 to 1,000 repeats.
This category of dynamic mutations is characterized by the following clinical conditions.
A. Fragile X Syndrome (Martin-Bell Syndrome).
1. Fragile X syndrome
is an X-linked recessive genetic disorder caused by a 200 to 1,000
unstable repeat sequence of (CGG)
n
outside the
FMR1 gene
on
chromosome X
for the
Fragile X mental retardation 1 protein (FMRP1,
a nucleocytoplasmic shuttling protein that
binds several mRNAs found abundantly in neurons.
2.
The 200 to 1,000
unstable repeat sequence of (CGG)
n
creates a fragile site on chromosome
X, which is observed when cells are cultured in a
folate-depleted
medium. The 200 to 1,000
unstable repeat sequence of (CGG)
n
has also been associated with
hypermethylation
of the
FMR1 gene so that FMRP1 is not expressed, which may lead to the phenotype of Fragile X.
3.
Fragile X syndrome involves two mutation sites.
Fragile X site A
involves a 200 to 1,000
unstable repeat sequence of (CGG)
n
located in a 5’ UTR of the
FMR 1 gene
on
chromosome
Xq27.3. Fragile X site B
involves a 200
unstable repeat sequence of (CCG)
n
located in a
promoter region of the
FMR 1 gene on chromosome Xq28.
4.
Normal FMR1 alleles have
5 to 40 repeats. They are stably transmitted without any
decrease or increase in repeat number.
5.
Premutation FMR1 alleles have
59 to 200 repeats. They are not stably transmitted. Females
with permutation FMR1 alleles are at risk for having children with Fragile X syndrome.
6. Prevalence.
The prevalence of Fragile X syndrome is 1/4,000 males. The prevalence of
Fragile X syndrome is 1/2,000 females.
7. Clinical features include:
mental retardation (most severe in males), macroorchidism (post-
pubertal), speech delay, behavioral problems (e.g., hyperactivity, attention deficit), prominent
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Chapter 5
Uniparental Disomy and Repeat Mutations
47
forehead and jaw, joint laxity, and large, dysmorphic ears. Fragile X syndrome is the second
leading cause of inherited mental retardation (Down syndrome is the number one cause).
B. Friedreich Ataxia (FRDA).
1.
FRDA is an autosomal recessive genetic disorder caused by a 600 to 1,200 unstable repeat
sequence of (GAA)
n
in intron 1 of the
FXN gene
on
chromosome 9q13-a21.1
for the
frataxin
protein, which is located on the inner mitochondrial membrane and plays a role in the
synthesis of respiratory chain complexes I through III , mitochondrial iron content, and
antioxidation defense.
2.
A longstanding hypothesis is that FRDA is a result of mitochondrial accumulation of iron,
which may promote oxidative stress injury.
3.
Normal FXN alleles have
5 to 33 repeats. They are stably transmitted without any
decrease or increase in repeat number.
4.
Premutation FXN alleles have
34 to 65 repeats. They are not stably transmitted.
Expansion of the permutation FXN alleles occurs during meiosis during the production of
both sperm (paternal transmission) and ova (maternal transmission) because
96% of
FRDA individuals are homozygous for the 600 to 1,200 unstable repeat sequence of (GAA)
n
.
5. Prevalence.
The prevalence of FRDA is 1/50,000.
6. Clinical features include:
degeneration of the posterior columns and spinocerebellar tracts,
loss of sensory neurons in the dorsal root ganglion, slowly progressive ataxia of all four limbs
with onset at 10 to 15 years of age, optic nerve atrophy, scoliosis, bladder dysfunction, swal-
lowing dysfunction, pyramidal tract disease, cardiomyopathy (arrhythmias), and diabetes.
C. Myotonic Dystrophy Type 1 (DM1).
1.
DM1 is an autosomal dominant genetic disorder caused by a
35 to 1,000 unstable repeat
sequence of (CTG)
n
in the 3’UTR region of the
DMPK gene
on
chromosome 19q13.2-q13.3
for
myotonin-protein kinase
which is a serine-threonine protein kinase associated with inter-
cellular conduction and impulse transmission in the heart and skeletal muscle.
2.
A hypothesis is that DM1 is caused by a gain-of-function RNA mechanism in which the
alternate splicing of other genes (e.g., Cl
ion channels, insulin receptor) occurs.
3.
Normal DMPK alleles have
5 to 35 repeats. They are stably transmitted without any
decrease or increase in repeat number.
4.
Premutation DMPK alleles have
35 to 49 repeats. They are not stably transmitted. Individuals
with permutation DMPK alleles are at risk for having children with DM1. A child with severe
DM1 (i.e., congenital DM1) most frequently inherits the expanded repeat from the mother.
5. Prevalence.
The prevalence of DM1 is 1/100,000 in Japan, 1/10,000 in Iceland, and
1/20,000 worldwide.
6. Clinical features include:
muscle weakness and wasting, myotonia (delayed muscle relax-
ation after contraction), cataracts, cardiomyopathy with conduction defects, multiple
endocrinopathies, age of onset is 2 to 30 years of age, and low intelligence or dementia.
IV. MODERATELY EXPANDED CAG REPEATS INSIDE THE GENE
In this category of dynamic mutation, a CAG repeat sequences undergoes moderate expan-
sions. Below threshold length, expansions are
10 to 30 repeats. Above threshold length,
expansions are
40 to 200 repeats. Because CAG codes for the amino acid
glutamine,
a long
tract of glutamines (polyglutamine tract) will be inserted into the amino acid sequence of the
protein and cause the protein to aggregate within certain cells. This category of dynamic
mutations is characterized by the following clinical conditions.
A. Huntington Disease (HD).
1.
HD is an autosomal dominant genetic disorder caused by a 36 S 100
unstable repeat
sequence of (CAG)
n
in the coding sequence of the HD
gene
on
chromosome 4p16.3
for the
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48
BRS Genetics
Huntington
protein, which is a widely expressed cytoplasmic protein present in neurons within
the striatum, cerebral cortex, and cerebellum, although its precise function is unknown.
2.
Because CAG codes for the amino acid glutamine, a long tract of glutamines (a polyglutamine
tract) will be inserted into the Huntington protein and cause protein aggregates to form within
certain cells (such as implicated in other neurodegenerative disorders).
3.
Normal HD alleles have
26 repeats. They are stably transmitted without any decrease or
increase in repeat number.
4.
Premutation HD alleles have 27 to 35 repeats. They are not stably transmitted. Individuals
with permutation HD alleles are at risk for having children with HD. A child with HD
inherits the expanded repeat from the father.
5.
An inverse correlation exists between the number of CAG repeats and the age of HD onset:
60 to 100 CAG repeats
juvenile onset of HD and 36 to 55 CAG repeats adult onset of HD.
6. Prevalence.
The prevalence of HD is 3 to 7/100,000 in populations of western European
descent. HD is less common in Japan, China, Finland, and Africa.
7. Clinical features include:
age of onset is 35 to 44 years of age, mean survival time is 15 to 18
years after onset, a movement jerkiness most apparent at movement termination, chorea
(dancelike movements), memory deficits, affective disturbances, personality changes,
dementia, diffuse and marked atrophy of the neostriatum due to cell death of cholinergic neu-
rons and GABA-ergic neurons within the striatum (caudate nucleus and putamen) and a rela-
tive increase in dopaminergic neuron activity, and neuronal intranuclear aggregates. The dis-
order is protracted and invariably fatal. In HD, homozygotes are not more severely affected by
the disorder than heterozygotes, which is an exception in autosomal dominant disorders.
B. Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome).
1.
SBMA is a X-linked recessive genetic disorder caused by a
38 repeat sequence of (CAG)
n
in the coding sequence of the
AR gene
on
chromosome Xq11-q12
for the
androgen receptor
which is a member of the steroid-thyroid-retinoid superfamily of nuclear receptors and
expressed in the brain, spinal cord, and muscle.
2.
A hypothesis is that SBMA is caused by a gain-of-function mutation because there is a
well-known syndrome called complete androgen insensitivity that is caused by a loss-of-
function mutation in the AR gene.
3.
Normal AR alleles have
34 repeats.
4.
Premutation AR alleles have not been reported to date.
5. Prevalence.
The prevalence of SBMA is
1/50,000 live males in the Caucasian and Asian
population. SBMA occurs only in males.
6. Clinical features include:
progressive loss of anterior motor neurons, proximal muscle
weakness, muscle atrophy, muscle fasciculations, difficulty in swallowing and speech
articulation, late-onset gynecomastia, defective spermatogenesis with reduced fertility,
testicular atrophy, and a hormonal profile consistent with androgen resistance.
C. Spinocerebellar Ataxia Type 3 (SCA3, Machado-Joseph Disease).
1.
SCA3 is an autosomal dominant genetic disorder caused a 52 to 86 repeat sequence of
(CAG)
n
in coding sequence of the
ATXN3 gene
on
chromosome 14q24.3-q31
for the
ataxin 3
protein, which is a ubiquitin-specific protease that binds and cleaves ubiquitin chains
and thereby participates in protein quality control pathways in the cell.
2.
A hypothesis is that SCA3 is caused by impaired protein clearance because mutant ataxin
3 forms nuclear inclusions that contain elements of the refolding and degradation
machinery of the cell (i.e., chaperone and proteosome subunits).
3.
Normal ATXN3 alleles have
44 repeats.
4.
Premutation ATXN3 alleles have not been reported to date.
5. Prevalence.
The prevalence of SCA3 in not known. Using a system based on genetic loci,
numerous autosomal dominant ataxias have been classified (SCA1-26) and the numbers
continue to grow. In general, all autosomal dominant ataxias are rare.
6. Clinical features include:
progressive cerebellar ataxia, dysarthria, bulbar dysfunction,
extrapyramidal features including rigidity and dystonia, upper and lower motor neuron
signs, cognitive impairments, age of onset is 20 to 50 years of age, individuals become
wheelchair bound, and nuclear inclusions are found.
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Chapter 5
Uniparental Disomy and Repeat Mutations
49
Mother
Father
Mother
Father
Mother
Father
Mother
Father
Nondisjunction
Nondisjunction
Ovum
Sperm
Ovum
Sperm
Ovum
Sperm
Ovum
Sperm
Nondisjunction
Nondisjunction
Normal
disjunction
Nondisjunction
Normal
disjunction
Nondisjunction
Zygote
Zygote
Embryonic cell
Embryonic cell
Trisomic zygote
Trisomic zygote
Fertilization
Fertilization
Fertilization
Fertilization
Cleavage
Maternal chromosome
loss
Cleavage
Paternal chromosome
loss
A
C
D
FIGURE 5-1. Uniparental disomy. (A)
Maternal nondisjunction produces an ovum with no copies of a specific chromosome
and paternal nondisjunction produces a sperm with two copies of the same chromosome. After fertilization, the zygote
has no copies of the maternal chromosome and two copies of the paternal chromosome. (B) Maternal nondisjunction pro-
duces an ovum with two copies of a specific chromosome and paternal nondisjunction produces a sperm with no copies
of the same chromosome. After fertilization, the zygote has two copies of the maternal chromosome and no copies of the
paternal chromosome. (C) Maternal disjunction produces an ovum with one copy of a specific chromosome and paternal
nondisjunction produces a sperm with two copies of the same chromosome. After fertilization, the zygote has three
copies of the same chromosome (i.e., a trisomic zygote). The maternal chromosome is lost during mitosis of the cleavage
stage, which produces embryonic cells with two copies of the paternal chromosome. (D) Maternal nondisjunction pro-
duces an ovum with two copies of a specific chromosome and paternal disjunction produces a sperm with one copy of
the same chromosome. After fertilization, the zygote has three copies of the same chromosome (i.e., a trisomic zygote).
The paternal chromosome is lost during mitosis of the cleavage stage, which produces embryonic cells with two copies
of the maternal chromosome. Maternal chromosomes
white, paternal chromosomes black.
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