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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
Q

Characterized by involuntary choreiform movements, cognitive impairment, and mood disorders and behavioral changes

A

Huntington’s disease

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26
Q

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
A
  1. ) 6-35 CAG repeats
  2. ) 36-39 CAG repeats
  3. ) More than 39 CAG repeats
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27
Q

Individuals who are borderline (“pre-mutation”) for Huntington’s are unaffected, but the tendency for expansion

A

Increases

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28
Q

If an individual has more than 39 CAG repeats in the HD gene, they are ALWAYS

A

Affected

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29
Q

Huntington’s shows paternal transmission because the repeat expansion occurs through

A

Spermatogenesis

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30
Q

The TNR expansion that causes Huntington’s can be detected by

-TNR expansion increases size of product

A

PCR

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31
Q

A polyglutamine disorder where TNR expansion occurs in the first exon leading to protein misfolding

-Displays AD inheritance with paternal expansion

A

Huntington’s Disease

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32
Q

The key clinical features of Huntington’s are

A

Chorea (movement disorder) or dystonia, abnormal eye movements, and dementia

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33
Q

The most common inherited cause of intellectual disability and autism spectral disorders

A

Fragile X Syndrome

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34
Q

What type of inheritance is seen in Fragile X Syndrome?

A

X-linked Dominant

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35
Q

Fragile X syndrome results from a mutation caused by unstable expansion of CGG in the promoter of the

A

Fragile X mental retardation gene (FMR1)

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36
Q

What are the prevalence characteristics of Fragile X syndrome?

A

Males are more likely to be affected and females are more likely to be carriers

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37
Q

What are some clinical characteristics of males affected with Fragile X syndrome?

A

Cognitive disability (low IQ), Long narrow face, Large everted ears, Hypotonia, and Macroorchidism

38
Q

Hyperextensible joints

39
Q

Large testicles (found in 90% of males with Fragile X syndrome)

A

Macroorchidism

40
Q

What percentage of males who carry the Fragile X premutation (20-200 repeats) are clinically normal?

41
Q

30-50% of carrier females with full mutation are affected (i.e. intellectually disabled) because of

A

Selective X-linked inactivation

42
Q

Highly conserved in the DNA form across species

A

FMR 1 gene

43
Q

For the FMR 1 gene, what si the:

  1. ) Normal form
  2. ) Pre-mutation form
  3. ) Full mutation form
A
  1. ) 6-55 CGG repeats
  2. ) 60-200 CGG repeats
    3) > 230-4000 CGG repeats
44
Q

The normal form of FMR 1 generally does not

45
Q

The premuation for of FMR 1 has a HIGH risk of expansion when transmitted by a

46
Q

An RNA binding protein that is a translational regulator of target mRNAs

-Functions as part of RISC complex

A

FMR protein

47
Q

A neuron with elongated, thinner, and denser dendritic spines indicates an

A

Immature stage of neuronal development

48
Q

Pre-mutation in FMR1 has which distinct clinical phenotype?

A

Tremor-Ataxia syndrome

49
Q

Is the risk for Fragile-X associated Tremor-Ataxia syndrome greater in males or in females?

50
Q

A progressive neurodegenerative disorder with late onset cerebellar ataxia

-Cognitive decline in elderly

A

Tremor-Ataxia Syndrome

51
Q

Another FMR1 pre-mutation phenotype characterized by cessation of menses before the age of 40

-affects 20% of females with pre-mutation

A

Primary ovarian insufficiency

52
Q

Full mutation results in methylation of the

-No protein produced

53
Q

A maternal TNR expansion in the 5’ UTR that displays x-linked inheritance

A

Fragile X syndrome

54
Q

AR disorder caused by unstable expansion of GAA in the first intron of the frataxin gene (FRDA)

A

Friedreich’s Ataxia

55
Q

The Frataxin gene (FDRA) encodes a

A

Mitochondrial protein

56
Q

Accounts for 50% of cases of hereditary ataxia

A

Friedreich’s Ataxia (FA)

57
Q

FA carrier rate has been estimated at 1 in 60 to 1 in 90, with a disease prevalence of

A

1 per 29,000

58
Q

How many GAA repeats indicate a normal frataxin gene?

A

6-32 repeats

59
Q

How many GAA repeats indicates Fridreich Ataxia?

A

200-1700 repeats

60
Q

TNR expansion of GAA in FDRA results in

-Intron is not properly spliced

A

mRNA transcript loss

61
Q

Frataxin likely plays a role in

A

Mitochondrial iron metabolism

62
Q

Results in mitochondrial dysfunction in the form of defective iron metabolism and defective heme and iron cluster synthesis

A

Loss of Frataxin

63
Q

Efpression of Frataxin is highest in the

A

Heart and Spinal Cord

64
Q

Results in selective cell loss in mitochondrial rich tissues such as dorsal root ganglion neurons, cardiomyocytes, and pancreatic beta cells

A

Frataxin Loss

65
Q

The presentation of FA correlates with

A

TNR number

-the higher TNR, the earlier the onset

66
Q

Characterized by ataxic gait initially, followed by progressive weakness in the extremities; dysarthria and dysphagia as well as cognitive dysfunction

A

Fridreich’s Ataxia

67
Q

An autosomal dominant disorder caused by an unstable expansion of CTG in the 3’ UTR region of the dystrophia myotonia protein kinase gene (DMPK)

A

Myotonic Dystrophy Type 1

68
Q

What type of inheritance pattern is displayed by Myotonic Dystrophy type 1?

A

Autosomal Dominant

69
Q

The most common cause of adult-onset muscular dystrophy

-occurance is 1 per 10,000

A

Myotonic Dystrophy Type 1

70
Q

The onset of Myotonic Dystrophy (MD) Type 1 is between

A

15 and 40 years

-can be present at birth

71
Q

How many CTC repeats characterize MD Type 1 alleles for:

  1. ) Normal alleles
  2. ) Mutable normal (premutation) alleles
  3. ) Full penetrance alleles
A
  1. ) 5-34 CTG repeats
  2. ) 35-49 CTG repeats
  3. ) > 50 CTG repeats
72
Q

The premutation for MD type 1 has no

A

Clinical phenotype

73
Q

What are the three overlapping phenotypes of MD type 1?

A

Mild (Late-onset/asymptomatic 50-150 repeats), Classic (adult onset 150-1000 repeats), and Severe (congenital >1000 repeats)

74
Q

Congenital (severe) type 1 is almost always inherited from the

75
Q

Both parents can transmit the TNR expansion up to 1,000 repeats, what is the difference between males and females after this point?

A

Males will not transmit expansion past this point, females will

76
Q

What is the molecular mechanism that explains the effects of trinucleotide repeat expansion in the 3’ UTR of the dystrophia myotonia kinase protein?

A

RNA-mediated toxicity

77
Q

Excess alternative mRNA splice isoforms are seen in

-decrease RNA stability

78
Q

MD type 1 displays RNA mediated pathogenesis. There is altered activity of RNA binding proteins regulating

79
Q

Characterized by an AD inheritance with maternal expansion for most severe phenotype

80
Q

The RNA toxicity in MD type 1 is due to sequestered

A

RNA splicing proteins

81
Q

Has the clinical features of adult onset muscular dystrophy, myotonia, type 2 diabetes, and cardiomyopathy

82
Q

Less TNR expansions are required to cause a disease if the expansion is in an

83
Q

Basically says that the more repeats you have, the younger the individual is when affected and the more severe the clinical phenotype is

A

Genetic Anticipation

84
Q

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

A

Huntington Protein

85
Q

Knocking out the Huntington protein does not cause

-Caused by aggregates

A

Clinical phenotype

86
Q

Involuntary movements are a hallmark of

A

Huntington’s

87
Q

Expansions in Huntington’s occur in

A

Spermatogenesis

88
Q

Expansions in Fragile X syndrome occur in the

89
Q

What are the two clinically significant levels of CGG (fragile X) expansion?

A
  1. ) >200 repeats = Full mutation

2. ) 55-200 repeats = pre-mutation

90
Q

What is the clinical triad of Friedrich’s Ataxia?

A
  1. ) Neurological dysfunction
  2. ) Cardiomyopathy
  3. ) Diabetes
91
Q

Has a full mutation at anything greater than 50 CTG repeats

A

Myotonic Dystrophy

92
Q

Severe myotonic dystrophy (>1000 repeats) is characterized by

A

Infantile Hypotonia

BMS (62 decks)

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