TY - JOUR
T1 - Somatic sequence variation at the Friedreich ataxia locus includes complete contraction of the expanded GAA triplet repeat, significant length variation in serially passaged lymphoblasts and enhanced mutagenesis in the flanking sequence
AU - Bidichandani, Sanjay I.
AU - Purandare, Smita M.
AU - Taylor, Ellen E.
AU - Gumin, Glenice
AU - Machkhas, Hazem
AU - Harati, Yadollah
AU - Gibbs, Richard A.
AU - Ashizawa, Tetsuo
AU - Patel, Pragna I.
N1 - Funding Information:
We are grateful to the patients and their families for participating in this study. We thank Darren G. Monckton, José M. Barral and Mehreen Hai for critically reviewing the manuscript and for their many helpful suggestions. This work was supported by grants from the Muscular Dystrophy Association (P.I.P. and S.I.B.), the March of Dimes Foundation (P.I.P. and S.I.B.), the Methodist Hospital Foundation (S.I.B.), the National Ataxia Foundation (S.I.B.) and the Oxnard Foundation through the National Ataxia Foundation (T.A.). Part of this work was carried out when S.I.B. was supported by a Post-doctoral Fellowship from the Muscular Dystrophy Association.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1999
Y1 - 1999
N2 - The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97-1250 triplets in lymphoblastoid cell lines passaged 20-39 times. Southern analyses revealed 18 events of significant changes in length ranging from 69 to 633 triplets, wherein the de novo allele gradually replaced the original over 1-6 passages. Contractions and expansions occurred with equal frequency and magnitude. This behavior is unique in comparison with other large, non-coding triplet repeat expansions [(CGG)(n) and (CTG)(n)] which remain relatively stable under similar conditions. We also report a rare patient who, having inherited two expanded alleles, showed evidence of contracted GAA repeats ranging from nine to 29 triplets in DNA from two independent peripheral blood samples. The GAA triplet repeat is known to adopt a triplex structure, and triplexes in transcribed templates cause enhanced mutagenesis. The poly(A) tract and a 135 bp sequence, both situated immediately upstream of the GAA triplet repeat, were therefore examined for somatic mutations. The poly(A) tract showed enhanced instability when in cis with the GAA expansion. The 135 bp upstream sequence was found to harbor a 3-fold excess of point mutations in DNA derived from individuals homozygous for the GAA triplet repeat expansion compared with normal controls. These data are likely to have important mechanistic and clinical implications.
AB - The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97-1250 triplets in lymphoblastoid cell lines passaged 20-39 times. Southern analyses revealed 18 events of significant changes in length ranging from 69 to 633 triplets, wherein the de novo allele gradually replaced the original over 1-6 passages. Contractions and expansions occurred with equal frequency and magnitude. This behavior is unique in comparison with other large, non-coding triplet repeat expansions [(CGG)(n) and (CTG)(n)] which remain relatively stable under similar conditions. We also report a rare patient who, having inherited two expanded alleles, showed evidence of contracted GAA repeats ranging from nine to 29 triplets in DNA from two independent peripheral blood samples. The GAA triplet repeat is known to adopt a triplex structure, and triplexes in transcribed templates cause enhanced mutagenesis. The poly(A) tract and a 135 bp sequence, both situated immediately upstream of the GAA triplet repeat, were therefore examined for somatic mutations. The poly(A) tract showed enhanced instability when in cis with the GAA expansion. The 135 bp upstream sequence was found to harbor a 3-fold excess of point mutations in DNA derived from individuals homozygous for the GAA triplet repeat expansion compared with normal controls. These data are likely to have important mechanistic and clinical implications.
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U2 - 10.1093/hmg/8.13.2425
DO - 10.1093/hmg/8.13.2425
M3 - Article
C2 - 10556290
AN - SCOPUS:0032739342
VL - 8
SP - 2425
EP - 2436
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 13
ER -