title: GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases.
abstract: We show that GAA instability in Friedreich's Ataxia is a DNA-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.
authors.affiliation: Department of Pharmacology, Mayo Foundation, Rochester, Minnesota 55905, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Gacy
authors.forename: G M
authors.initials: GM
authors.lastname: Goellner
authors.forename: C
authors.initials: C
authors.lastname: Spiro
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Gupta
authors.forename: E M
authors.initials: EM
authors.lastname: Bradbury
authors.forename: R B
authors.initials: RB
authors.lastname: Dyer
authors.forename: M J
authors.initials: MJ
authors.lastname: Mikesell
authors.forename: J Z
authors.initials: JZ
authors.lastname: Yao
authors.forename: A J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: S B
authors.initials: SB
authors.lastname: Melançon
authors.forename: C T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005192:Family Health; D005621:Friedreich Ataxia / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D010375:Pedigree; D011995:Recombination, Genetic; D018911:Trinucleotide Repeats
chemical_list: D004247:DNA; D004259:DNA-Directed DNA Polymerase