Lecture 8: Repeat Expansion Disorders Flashcards
What is genetic anticipation?
Disease getting worse as you go down generations
What was genetic anticipation noted in fragile X?
1985 by Sherman
How many humans repeat expansion diseases are known to date?
Approx 50
How many types of repeats that may be expanded can cause disease?
13
Do all repeat expansion disorders show genetic anticipation?
no
What are the four mechanism that cause disease in repeat expansion?
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.
What is an example of expansion of non-coding repeats leading to loss of function of gene containing repeat disease?
Fragile X
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?
Huntingtons
Kennedys
What are examples of Expansions resulting in gain of function of RNA containing an expanded repeat diseases?
Myotonic dystrophy 1 and 2
Fragile X associated tremor ataxia syndrome
Fragile X associated premature ovarian insufficiency
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?
ALS
Describe some features associated with Fragile X syndrome
Intellectual disability
Higher severity in males
Cause of autism
What the gene location associated with fragile X?
Xq27.3
What gene is associated with fragile X?
FRAXA site in FMR1 gene
What repeats are expanded in fragile X syndrome?
CGG in the 5’ UTR
What is the range of stable repeats in fragile X?
6-44
What is the range of intermediate repeats in fragile X?
45-54
What is the range of permeation repeats in fragile X?
55-200
What is the range for full FRAX mutation in fragile X?
200- over 4000
What diseases are associated with the premuation repeat range of fragile X?
FXTAS
FXPOI
How does expanded reads cause fragile X syndrome?
Expanded repeat transcript interacts back with expanded repeats in DNA and creates silencing by methylation of CG.This causes the loss of FMRP
What is the normal role of FMRP?
Prevents translation of target dendritic mRNAs
What trinucleotide expansion is Huntington’s disease caused by?
CAG
What is the normal allele repeat range for CAG?
11-26
What is the mutable normal allele range of CAG?
27- 35
What is the HD allele with reduced penetrate range of CAG repeats?
36-39
What is the full HD allele penetrate from CAG repeat range?
39- over 200
What geen is afetend in Huntington disease?
HTT
Where are high levels of HTT normally found?
Neurones of CNS
How does mutant HTT protein result in pathology?
Generates toxic fragments with abnormal conformation
What is the normal role of HTT?
Acts as scaffold to coordinate complexes of other proteins
Acts as transcriptional regulator
