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The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions.

Abstract：

:Friedreich ataxia is commonly caused by large expansions of a GAA triplet-repeat (GAA-TR) sequence in the first intron of the FRDA gene. We used small-pool PCR to analyze somatic variability among 7190 individual FRDA molecules from peripheral blood DNA of subjects carrying 12 different expanded alleles, ranging in size from 241 to 1105 triplets. Expanded alleles showed a length-dependent increase in somatic variability, with mutation loads ranging from 47% to 78%. We noted a strong contraction bias among long alleles (>500 triplets), which showed a 4-fold higher frequency of large contractions versus expansions. Some contractions were very large; of all somatic mutations scored, approximately 5% involved contractions of >50% of the original allele length, and 0.29% involved complete reversion to the normal/premutation length (< or =60 triplets). These observations contrast sharply with the strong expansion bias seen in expanded CTG triplet repeats in myotonic dystrophy. No somatic variability was detected in >6000 individual FRDA molecules analyzed from 15 normal alleles (8-25 triplets). A premutation allele with 44 uninterrupted GAA repeats was found to be unstable, ranging in size from 6 to 113 triplets, thus establishing the threshold for somatic instability between 26 and 44 GAA triplets. Analysis of an additional 7850 FRDA molecules from serially passaged lymphoblastoid cell lines carrying nine expanded alleles (132-933 triplets) showed very low mutation loads, ranging from 0% to 6.2%. Our data indicate that expanded GAA-TR alleles in Friedreich ataxia are highly mutable and have a natural tendency to contract in vivo, and that these properties depend on multiple factors, including DNA sequence, triplet-repeat length and unknown cell-type-specific factors.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Sharma R,Bhatti S,Gomez M,Clark RM,Murray C,Ashizawa T,Bidichandani SI

doi

10.1093/hmg/11.18.2175

subject

Has Abstract

pub_date

2002-09-01 00:00:00

pages

2175-87

issue

eissn

0964-6906

issn

1460-2083

journal_volume

pub_type

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The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions.