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Trinucleotide Repeat (TNR) Expansion Disorders Flashcards

1
Q

Repeating sequences of three nucleotides that can occur anywhere in the genome

A

Trinucleotide repeats

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2
Q

Repeated numbers normally stay relatively constant during

A

Replication

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3
Q

Replication errors can cause repeat numbers to

A

Expand

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4
Q

We don’t know why trinucleotide repeats expand, but a hallmark feature is

-Ex: polymerase slippage

A

Instability

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5
Q

Expansion of trinucleotide repeats leads to genetic disorders with

A

Non-Mendelian inheritance patterns

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6
Q

The molecular characteristics and consequences of trinucleotide expansions (TNRs)

A

Differ

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7
Q

The tendency for repeat TNR expansion depends on the

A

Transmitting parent

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8
Q

Individuals with an abnormal number of TNRs who have fewer or no symptoms are said to carry

A

“Pre-mutations”

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9
Q

TNR Disorders display

A

“Genetic Anticipation”

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10
Q

Trinucleotide expansion in the coding region causes the polyglutamine diseases

A

Huntington’s and Spinocerebellar Ataxia

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11
Q

The polyglutamine diseases are caused by an excess of misfolded protein due to

A

Glutamine Insertions

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12
Q

Which two diseases are caused by TNR in the Non-coding region?

A

Friedreich’s Ataxia and “Fragile X” syndrome

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13
Q

Diseases caused by TNR expansion in the non-coding region (Friedreich’s Ataxia and “Fragile X” syndrome) are caused by

A

Diminished or absent protein(s)

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14
Q

Fragile X syndrome is due to a TNR on FMR1. What is the premutation genotype?

A

(CGG)n where n is greater than 55 but less than 200

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15
Q

If there are less than 55 CGG repeats in FMR1 than the individual is

A

Normal

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16
Q

If there are more than 200 CGG TNRs in FMR1 than the individual has

A

“Fragile X syndrome”

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17
Q

As TNRs expand with subsequent generations, the disease

A

Presents at an earlier age and becomes more severe

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18
Q

What are three hallmarks of Huntington’s Disease?

A
  1. ) Saccadic extraocular eye movements
  2. ) Increased tone in extremities
  3. ) Wide-based and ataxic gait
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19
Q

An autosomal dominant neurodegenerative disorder

A

Huntington’s Disease

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20
Q

Huntington’s is caused by mutations in the first exon of the Huntington protein, resulting in an increase in

A

Glutamines

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21
Q

The increase in glutamines caues the Huntington protein to

A

Aggregate

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22
Q

The protein aggregates overwhelm the ubiquitin-proteasome system and cause

A

Neuronal toxicity

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23
Q

What is the population frequency of Huntington’s disease?

A

3-7/100,000

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24
Q

The typical onset of Huntington’s is in

-Duration is typically 15-20 years from the time of onset

A

Midlife

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25
Characterized by involuntary choreiform movements, cognitive impairment, and mood disorders and behavioral changes
Huntington's disease
26
For Huntington's, what number of CAG repeats in the HD gene characterizes: 1. ) Normal HD gene 2. ) Borderline ("Pre-mutation) HD gene 3. ) Disease Phenotype
1. ) 6-35 CAG repeats 2. ) 36-39 CAG repeats 3. ) More than 39 CAG repeats
27
Individuals who are borderline ("pre-mutation") for Huntington's are unaffected, but the tendency for expansion
Increases
28
If an individual has more than 39 CAG repeats in the HD gene, they are ALWAYS
Affected
29
Huntington's shows paternal transmission because the repeat expansion occurs through
Spermatogenesis
30
The TNR expansion that causes Huntington's can be detected by -TNR expansion increases size of product
PCR
31
A polyglutamine disorder where TNR expansion occurs in the first exon leading to protein misfolding -Displays AD inheritance with paternal expansion
Huntington's Disease
32
The key clinical features of Huntington's are
Chorea (movement disorder) or dystonia, abnormal eye movements, and dementia
33
The most common inherited cause of intellectual disability and autism spectral disorders
Fragile X Syndrome
34
What type of inheritance is seen in Fragile X Syndrome?
X-linked Dominant
35
Fragile X syndrome results from a mutation caused by unstable expansion of CGG in the promoter of the
Fragile X mental retardation gene (FMR1)
36
What are the prevalence characteristics of Fragile X syndrome?
Males are more likely to be affected and females are more likely to be carriers
37
What are some clinical characteristics of males affected with Fragile X syndrome?
Cognitive disability (low IQ), Long narrow face, Large everted ears, Hypotonia, and Macroorchidism
38
Hyperextensible joints
Hypotonia
39
Large testicles (found in 90% of males with Fragile X syndrome)
Macroorchidism
40
What percentage of males who carry the Fragile X premutation (20-200 repeats) are clinically normal?
20%
41
30-50% of carrier females with full mutation are affected (i.e. intellectually disabled) because of
Selective X-linked inactivation
42
Highly conserved in the DNA form across species
FMR 1 gene
43
For the FMR 1 gene, what si the: 1. ) Normal form 2. ) Pre-mutation form 3. ) Full mutation form
1. ) 6-55 CGG repeats 2. ) 60-200 CGG repeats 3) > 230-4000 CGG repeats
44
The normal form of FMR 1 generally does not
Expand
45
The premuation for of FMR 1 has a HIGH risk of expansion when transmitted by a
Female
46
An RNA binding protein that is a translational regulator of target mRNAs -Functions as part of RISC complex
FMR protein
47
A neuron with elongated, thinner, and denser dendritic spines indicates an
Immature stage of neuronal development
48
Pre-mutation in FMR1 has which distinct clinical phenotype?
Tremor-Ataxia syndrome
49
Is the risk for Fragile-X associated Tremor-Ataxia syndrome greater in males or in females?
Males
50
A progressive neurodegenerative disorder with late onset cerebellar ataxia -Cognitive decline in elderly
Tremor-Ataxia Syndrome
51
Another FMR1 pre-mutation phenotype characterized by cessation of menses before the age of 40 -affects 20% of females with pre-mutation
Primary ovarian insufficiency
52
Full mutation results in methylation of the -No protein produced
FMR gene
53
A maternal TNR expansion in the 5' UTR that displays x-linked inheritance
Fragile X syndrome
54
AR disorder caused by unstable expansion of GAA in the first intron of the frataxin gene (FRDA)
Friedreich's Ataxia
55
The Frataxin gene (FDRA) encodes a
Mitochondrial protein
56
Accounts for 50% of cases of hereditary ataxia
Friedreich's Ataxia (FA)
57
FA carrier rate has been estimated at 1 in 60 to 1 in 90, with a disease prevalence of
1 per 29,000
58
How many GAA repeats indicate a normal frataxin gene?
6-32 repeats
59
How many GAA repeats indicates Fridreich Ataxia?
200-1700 repeats
60
TNR expansion of GAA in FDRA results in -Intron is not properly spliced
mRNA transcript loss
61
Frataxin likely plays a role in
Mitochondrial iron metabolism
62
Results in mitochondrial dysfunction in the form of defective iron metabolism and defective heme and iron cluster synthesis
Loss of Frataxin
63
Efpression of Frataxin is highest in the
Heart and Spinal Cord
64
Results in selective cell loss in mitochondrial rich tissues such as dorsal root ganglion neurons, cardiomyocytes, and pancreatic beta cells
Frataxin Loss
65
The presentation of FA correlates with
TNR number -the higher TNR, the earlier the onset
66
Characterized by ataxic gait initially, followed by progressive weakness in the extremities; dysarthria and dysphagia as well as cognitive dysfunction
Fridreich's Ataxia
67
An autosomal dominant disorder caused by an unstable expansion of CTG in the 3' UTR region of the dystrophia myotonia protein kinase gene (DMPK)
Myotonic Dystrophy Type 1
68
What type of inheritance pattern is displayed by Myotonic Dystrophy type 1?
Autosomal Dominant
69
The most common cause of adult-onset muscular dystrophy -occurance is 1 per 10,000
Myotonic Dystrophy Type 1
70
The onset of Myotonic Dystrophy (MD) Type 1 is between
15 and 40 years -can be present at birth
71
How many CTC repeats characterize MD Type 1 alleles for: 1. ) Normal alleles 2. ) Mutable normal (premutation) alleles 3. ) Full penetrance alleles
1. ) 5-34 CTG repeats 2. ) 35-49 CTG repeats 3. ) > 50 CTG repeats
72
The premutation for MD type 1 has no
Clinical phenotype
73
What are the three overlapping phenotypes of MD type 1?
Mild (Late-onset/asymptomatic 50-150 repeats), Classic (adult onset 150-1000 repeats), and Severe (congenital >1000 repeats)
74
Congenital (severe) type 1 is almost always inherited from the
Mother
75
Both parents can transmit the TNR expansion up to 1,000 repeats, what is the difference between males and females after this point?
Males will not transmit expansion past this point, females will
76
What is the molecular mechanism that explains the effects of trinucleotide repeat expansion in the 3' UTR of the dystrophia myotonia kinase protein?
RNA-mediated toxicity
77
Excess alternative mRNA splice isoforms are seen in -decrease RNA stability
MD type 1
78
MD type 1 displays RNA mediated pathogenesis. There is altered activity of RNA binding proteins regulating
Splicing
79
Characterized by an AD inheritance with maternal expansion for most severe phenotype
MD type 1
80
The RNA toxicity in MD type 1 is due to sequestered
RNA splicing proteins
81
Has the clinical features of adult onset muscular dystrophy, myotonia, type 2 diabetes, and cardiomyopathy
MD type 1
82
Less TNR expansions are required to cause a disease if the expansion is in an
Exon
83
Basically says that the more repeats you have, the younger the individual is when affected and the more severe the clinical phenotype is
Genetic Anticipation
84
Widely expressed in the brain and body, but pathologically is restricted to the CNS -Aggregates form that modify transcription, inuce proteolysis, interfere w/ axonal transport, and disrupt synaptic transmission
Huntington Protein
85
Knocking out the Huntington protein does not cause -Caused by aggregates
Clinical phenotype
86
Involuntary movements are a hallmark of
Huntington's
87
Expansions in Huntington's occur in
Spermatogenesis
88
Expansions in Fragile X syndrome occur in the
Oocyte
89
What are the two clinically significant levels of CGG (fragile X) expansion?
1. ) >200 repeats = Full mutation | 2. ) 55-200 repeats = pre-mutation
90
What is the clinical triad of Friedrich's Ataxia?
1. ) Neurological dysfunction 2. ) Cardiomyopathy 3. ) Diabetes
91
Has a full mutation at anything greater than 50 CTG repeats
Myotonic Dystrophy
92
Severe myotonic dystrophy (>1000 repeats) is characterized by
Infantile Hypotonia

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