Lecture 8: Repeat Expansion Disorders

Question 1

What is genetic anticipation?

Answer 1

Disease getting worse as you go down generations

Question 2

What was genetic anticipation noted in fragile X?

Answer 2

1985 by Sherman

Question 3

How many humans repeat expansion diseases are known to date?

Answer 3

Approx 50

Question 4

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

Answer 4

13

Question 5

Do all repeat expansion disorders show genetic anticipation?

Answer 5

no

Question 6

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

Answer 6

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.

Question 7

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

Answer 7

Fragile X

Question 8

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?

Answer 8

Huntingtons

Kennedys

Question 9

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

Answer 9

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

Question 10

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?

Answer 10

ALS

Question 11

Describe some features associated with Fragile X syndrome

Answer 11

Intellectual disability
Higher severity in males
Cause of autism

Question 12

What the gene location associated with fragile X?

Answer 12

Xq27.3

Question 13

What gene is associated with fragile X?

Answer 13

FRAXA site in FMR1 gene

Question 14

What repeats are expanded in fragile X syndrome?

Answer 14

CGG in the 5’ UTR

Question 15

What is the range of stable repeats in fragile X?

Answer 15

6-44

Question 16

What is the range of intermediate repeats in fragile X?

Answer 16

45-54

Question 17

What is the range of permeation repeats in fragile X?

Answer 17

55-200

Question 18

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

Answer 18

200- over 4000

Question 19

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

Answer 19

FXTAS

FXPOI

Question 20

How does expanded reads cause fragile X syndrome?

Answer 20

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

Question 21

What is the normal role of FMRP?

Answer 21

Prevents translation of target dendritic mRNAs

Question 22

What trinucleotide expansion is Huntington’s disease caused by?

Answer 22

CAG

Question 23

What is the normal allele repeat range for CAG?

Answer 23

11-26

Question 24

What is the mutable normal allele range of CAG?

Answer 24

27- 35

Question 25

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

Answer 25

36-39

Question 26

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

Answer 26

39- over 200

Question 27

What geen is afetend in Huntington disease?

Answer 27

HTT

Question 28

Where are high levels of HTT normally found?

Answer 28

Neurones of CNS

Question 29

How does mutant HTT protein result in pathology?

Answer 29

Generates toxic fragments with abnormal conformation

Question 30

What is the normal role of HTT?

Answer 30

Acts as scaffold to coordinate complexes of other proteins

Acts as transcriptional regulator