THE FRIEDREICH ATAXIA GAA TRIPLET REPEAT - PREMUTATION AND NORMAL ALLELES

The most common mutation causing Friedreich ataxia (FRDA), an autosoma l recessive neurodegenerative disease, is the hyperexpansion of a poly morphic GAA triplet repeat localized within an Alu sequence (GAA-Alu) in the first intron of the frataxin (X25) gene. GAA-Alu belongs to the AluSx subfamily and contains several polymorphisms in strong linkage disequilibrium either with a subgroup of normal alleles, or with hyper expanded FRDA-associated alleles. GAA repeat sizes in 300 normal chrom osomes (97 from carriers and 203 from controls) were distributed in tw o separate groups: 83% of them contained between six and 10 triplets ( small normal alleles), while the remaining 17% had more than 12 triple ts, up to 36 (large normal alleles). Sequence analysis showed that no normal, stable allele contained more than 27 uninterrupted GAA triplet s. All longer normal alleles were interrupted by a hexanucleotide repe at (GAGGAA). An allele containing an uninterrupted run of 34 GAA tripl ets was stably transmitted in four instances, but in one case underwen t hyperexpansion to 650 triplets. Overall, our results suggest that th e FRDA-associated expanded GAA repeats originate from normal alleles b y recurrent expansions of alleles at risk.