GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases

A. Marquis Gacy, Geoffrey M. Goellner, Craig Spiro, Xian Chen, Goutam Gupta, E. Morton Bradbury, Roy B. Dyer, Marci J. Mikesell, Janet Z. Yao, Aaron J. Johnson, Andrea Richter, Serge B. Melançon, Cynthia T. McMurray

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

We show that GAA instability in Friedreich's Ataxia is a DMA-directed mutation caused by improper DNA structure at the repeat region. Unlike CAG or CGG repeats, which form hairpins, GAA repeats form a YRY triple helix containing non-Watson-Crick pairs. As with hairpins, triplex mediates intergenerational instability in 96% of transmissions. In families with Friedreich's Ataxia, the only recessive trinucleotide disease, GAA instability is not a function of the number of long alleles, ruling out homologous recombination or gene conversion as a major mechanism. The similarity of mutation pattern among triple repeat-related diseases indicates that all trinucleotide instability occurs by a common, intraallelic mechanism that depends on DNA structure. Secondary structure mediates instability by creating strong polymerase pause sites at or within the repeats, facilitating slippage or sister chromatid exchange.

Original languageEnglish (US)
Pages (from-to)583-593
Number of pages11
JournalMolecular Cell
Volume1
Issue number4
DOIs
StatePublished - Mar 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Gacy, A. M., Goellner, G. M., Spiro, C., Chen, X., Gupta, G., Bradbury, E. M., Dyer, R. B., Mikesell, M. J., Yao, J. Z., Johnson, A. J., Richter, A., Melançon, S. B., & McMurray, C. T. (1998). GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases. Molecular Cell, 1(4), 583-593. https://doi.org/10.1016/S1097-2765(00)80058-1