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Diseases of the Nervous System > Unstable DNA and Simple Repeat Expansions > Flashcards

Unstable DNA and Simple Repeat Expansions Flashcards

1
Q

What causes variable symptoms in diseases caused by repeat expansions?

A

Variation in repeat length.

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2
Q

What are the features of spinocerebellar ataxia type 7?

A 
Atxia of both gait and limbs
 - neuronal degeneration associated with: 
dysarthria, lower limb spasticity
dysphagia, oculomotor abnormalities,
myokymia, mental impairment.

Retinal degeneration:

  • bilateral, symmetrical
  • leads to blindness
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3
Q

What is the age of onset of spinocerebellar ataxia type 7?

A

0-60 mean is 29

Striking anticipation

Onset to death: few years for early onset, up to 30 years for late onset.

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4
Q

What is the inheritance pattern for spinocerebellar ataxia type 7?

A

Autosomal dominant

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5
Q

What is spinocerebellar ataxia type 7 caused by?

A

CAG repeat:
6-19 repeats in normal population
about 75% alleles have 10 repeats
Heterozygosity about 35%

Disease phenotype:
37-306 repeats
Average about 55 repeats
Larger alleles - increased severity, decreased age of onset.

Intermediate alleles  (28-35):
Not associated with disease, risk of expansion in succeeding generations.
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6
Q

Is there transmission bias in SCA7 families?

A

Yes, most transmissions are from affected mothers.

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7
Q

What is the mutation rate in the sperm of SCA7 male?

A

100%

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8
Q

Name 4 expanded polyglutamine repeat disorders.

A

Spinal and bulbar muscular dystrophy
Huntington disease
Spinocerebellar ataxia (SCA) types 1, 2, 3, 7 and 17
Dentatorubral pallidoluysian atrophy

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9
Q

What is happening in polyglutamine repeat disorders?

A

Gain of function of polyglutamine tract - protein aggregates.

Mitochondrial dysfunction
Proteosome dysfunction
Transcriptional mis-regulation
Induction of apoptotic pathway

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10
Q

What are the clinical features of myotonic dystrophy?

A 
Cataracts
Heart conduction defects
Brain dysfunction
Gastrointestinal tract dysfunction
Insulin resistance
Frontal balding in males
Testicular atrophy
Muscular atrophy
Myotonia
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11
Q

What is the inheritance pattern of myotonic dystrophy?

A

Autosomal dominant - anticipation

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12
Q

What is the repeat expansion in myotonic dystrophy?

A

CTG

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13
Q

Are most congenital cases of myotonic dystrophy inherited from mother or father?

A

Mother

Excess of transmitting grandfathers.

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14
Q

What is SIX5?

A

A homeodomain transcription factor.
It is widely expressed at low levels, but highly expressed in the eye.
Reduction in expression is caused by mutant chromosome in DM - chromatin condensation in region of repeat.

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15
Q

Which gene is differentially spliced in myotonic dystrophy muscle?

A

CLC1

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16
Q

What are the therapeutic opportunities in DM?

A

Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA (read this paper).

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17
Q

What is Friedreich ataxia?

A

Progressive neurodegeneration of both central and peripheral nervous system.

Ataxia of gait
Dysarthria
Hypertrophic cardiomyopathy
Diabetes mellitus

18
Q

What is the inheritance pattern in Friedreich ataxia?

A

Autosomal recessive.

19
Q

Which nucleotide sequence is repeated in FA?

A

GAA

20
Q

In FA if 96% of patients are homozygous for GAA mutation what is happening in the other 4%?

A

Compound heterozygotes for point mutations:
Premature stops
Missense mutations
Loss of function

21
Q

What kind of structures can polypurine sequences (such as GAA) form?

A

Triplex DNA

  • no evidence for their existence in vivo
  • do block transcription in vitro
  • frataxin transcript levels reduced in patients.
22
Q

Where is frataxin highly expressed?

A

Neurons
Cardiomyocytes
Pancreas
Skeletal muscle

23
Q

What is frataxin?

A

A mitochondrial membrane protein.

24
Q

What is frataxin involved in?

A

Intracellular iron homeostasis
Iron accumulates in mitochondria
Cells are susceptible to free radical change.

25
Q

Have any animal models been made to study FXN?

A

Yes, mouse models using cre-lox.

Splice out fourth exon.

26
Q

What is the phenotype of fxn mouse models?

A 
Lose weight at 7 weeks
Progressively develop signs of fatigue.
Die at about 11 weeks
Develop cardiomyopathy
 - degenerating mitochondria
 - iron deposits
No skeletal muscle defects
27
Q

What is the clinical presentation of fragile X syndrome?

A 
Mental retardation
Long faces
Prominent ears
Autistic like behaviour
 - no neurodegeneration
 - aberrant dendritic structures - excess dendrites (no pruning)
28
Q

What can be seen on a karyotype of a patient with fragile X syndrome?

A

Observable fragile site on the long arm of the X chromosome.
Only visible in specific in vitro tissue culture conditions.

29
Q

What is the incidence of fragile X?

A

1/1,500

30
Q

Are males or females with fragile X more severely affected?

A

Males

31
Q

What is the inheritance pattern of fragile X?

A

X-linked

32
Q

What is unusual about the inheritance of fragile X?

A

Men with mutant chromosome don’t always have the phenotype.
Penetrance increases through generations.
Severity is always the same.
Due to triplet repeat.

33
Q

Which triplet is repeated in fragile X?

A

CGG

34
Q

How many CGG repeats are found in the general population and in fragile X?

A

General population 5-45
Affected patients 230-2000
Normal transmitting male 50-200

35
Q

What does the CGG repeat cause?

A

Hypermethylation (CpG island) resulting in transcriptional repression.
Therefore no FRM1 mRNA produced.
no FMRP produced in males

36
Q

Do normally transmitting males have any symptoms?

A

Can be prone to late onset tremor/ataxia.

37
Q

How does repeat length change in fragile X if it’s repeated by males vs females?

A

Repeat increases down the generations if transmitted by females.
Not so much if transmitted by males.

38
Q

In which gene is the CGG expansion in fragile X?

A

FMR1

39
Q

Which region of FMR1 is the CGG expansion found?

A

5’ untranslated region.

40
Q

What is FMRP?

A

Translational repressor
Associated with transcripts that are spatially translated.
In neurons translation often only occurs in end of synapses

41
Q

Which mRNAs are affected by fragile X?

A

SEC7
SAPAP4, DAP-1, kinate receptor
GRMs - metabolic glutamate receptors involved in long term potentiation.

Diseases of the Nervous System (15 decks)

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