Trinucleotide Repeat (TNR) Expansion Disorders Flashcards Preview

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Flashcards in Trinucleotide Repeat (TNR) Expansion Disorders Deck (92):
1

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

Trinucleotide repeats

2

Repeated numbers normally stay relatively constant during

Replication

3

Replication errors can cause repeat numbers to

Expand

4

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

-Ex: polymerase slippage

Instability

5

Expansion of trinucleotide repeats leads to genetic disorders with

Non-Mendelian inheritance patterns

6

The molecular characteristics and consequences of trinucleotide expansions (TNRs)

Differ

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The tendency for repeat TNR expansion depends on the

Transmitting parent

8

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

"Pre-mutations"

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TNR Disorders display

"Genetic Anticipation"

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Trinucleotide expansion in the coding region causes the polyglutamine diseases

Huntington's and Spinocerebellar Ataxia

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

Glutamine Insertions

12

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

Friedreich's Ataxia and "Fragile X" syndrome

13

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

Diminished or absent protein(s)

14

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

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

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

Normal

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

"Fragile X syndrome"

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As TNRs expand with subsequent generations, the disease

Presents at an earlier age and becomes more severe

18

What are three hallmarks of Huntington's Disease?

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

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An autosomal dominant neurodegenerative disorder

Huntington's Disease

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

Glutamines

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The increase in glutamines caues the Huntington protein to

Aggregate

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The protein aggregates overwhelm the ubiquitin-proteasome system and cause

Neuronal toxicity

23

What is the population frequency of Huntington's disease?

3-7/100,000

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The typical onset of Huntington's is in

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

Midlife

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

Huntington's disease

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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

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

Spermatogenesis

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

-TNR expansion increases size of product

PCR

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

-Displays AD inheritance with paternal expansion

Huntington's Disease

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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

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What type of inheritance is seen in Fragile X Syndrome?

X-linked Dominant

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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

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

Macroorchidism

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

20%

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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

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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

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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

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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)

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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

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How many GAA repeats indicates Fridreich Ataxia?

200-1700 repeats

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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

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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

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

MD type 1

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

Exon

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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

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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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