Lecture 8: Repeat Expansion Disorders Flashcards Preview

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Flashcards in Lecture 8: Repeat Expansion Disorders Deck (30)
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1
Q

What is genetic anticipation?

A

Disease getting worse as you go down generations

2
Q

What was genetic anticipation noted in fragile X?

A

1985 by Sherman

3
Q

How many humans repeat expansion diseases are known to date?

A

Approx 50

4
Q

How many types of repeats that may be expanded can cause disease?

A

13

5
Q

Do all repeat expansion disorders show genetic anticipation?

A

no

6
Q

What are the four mechanism that cause disease in repeat expansion?

A

Expansion of non-coding repeats leading to loss of function of gene containing repeat
Expansions of CAG coding repeats leading to gain of function (gof) and production of abnormal protein containing an expanded polyglutamine tract
Expansions resulting in gain of function of RNA containing an expanded repeat
Expansions resulting in Repeat Associated, Non-ATG (RAN) translation of repeat containing RNA leading to production of toxic peptides.

7
Q

What is an example of expansion of non-coding repeats leading to loss of function of gene containing repeat disease?

A

Fragile X

8
Q

What are examples of expansions of CAG coding repeats leading to gain of function (gof) and production of abnormal protein containing an expanded polyglutamine tract diseases?

A

Huntingtons

Kennedys

9
Q

What are examples of Expansions resulting in gain of function of RNA containing an expanded repeat diseases?

A

Myotonic dystrophy 1 and 2
Fragile X associated tremor ataxia syndrome
Fragile X associated premature ovarian insufficiency

10
Q

What is an example of Expansions resulting in Repeat Associated, Non-ATG (RAN) translation of repeat containing RNA leading to production of toxic peptides disease?

A

ALS

11
Q

Describe some features associated with Fragile X syndrome

A

Intellectual disability
Higher severity in males
Cause of autism

12
Q

What the gene location associated with fragile X?

A

Xq27.3

13
Q

What gene is associated with fragile X?

A

FRAXA site in FMR1 gene

14
Q

What repeats are expanded in fragile X syndrome?

A

CGG in the 5’ UTR

15
Q

What is the range of stable repeats in fragile X?

A

6-44

16
Q

What is the range of intermediate repeats in fragile X?

A

45-54

17
Q

What is the range of permeation repeats in fragile X?

A

55-200

18
Q

What is the range for full FRAX mutation in fragile X?

A

200- over 4000

19
Q

What diseases are associated with the premuation repeat range of fragile X?

A

FXTAS

FXPOI

20
Q

How does expanded reads cause fragile X syndrome?

A

Expanded repeat transcript interacts back with expanded repeats in DNA and creates silencing by methylation of CG.This causes the loss of FMRP

21
Q

What is the normal role of FMRP?

A

Prevents translation of target dendritic mRNAs

22
Q

What trinucleotide expansion is Huntington’s disease caused by?

A

CAG

23
Q

What is the normal allele repeat range for CAG?

A

11-26

24
Q

What is the mutable normal allele range of CAG?

A

27- 35

25
Q

What is the HD allele with reduced penetrate range of CAG repeats?

A

36-39

26
Q

What is the full HD allele penetrate from CAG repeat range?

A

39- over 200

27
Q

What geen is afetend in Huntington disease?

A

HTT

28
Q

Where are high levels of HTT normally found?

A

Neurones of CNS

29
Q

How does mutant HTT protein result in pathology?

A

Generates toxic fragments with abnormal conformation

30
Q

What is the normal role of HTT?

A

Acts as scaffold to coordinate complexes of other proteins

Acts as transcriptional regulator