GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases.
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.
Gacy
A M
AM
Department of Pharmacology, Mayo Foundation, Rochester, Minnesota 55905, USA.
Goellner
G M
GM
Spiro
C
C
Chen
X
X
Gupta
G
G
Bradbury
E M
EM
Dyer
R B
RB
Mikesell
M J
MJ
Yao
J Z
JZ
Johnson
A J
AJ
Richter
A
A
Melançon
S B
SB
McMurray
C T
CT
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
D004247:DNA; D004259:DNA-Directed DNA Polymerase