title: The Friedreich ataxia GAA triplet repeat: premutation and normal alleles.
abstract: The most common mutation causing Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease, is the hyperexpansion of a polymorphic 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 hyperexpanded FRDA-associated alleles. GAA repeat sizes in 300 normal chromosomes (97 from carriers and 203 from controls) were distributed in two separate groups: 83% of them contained between six and 10 triplets (small normal alleles), while the remaining 17% had more than 12 triplets, up to 36 (large normal alleles). Sequence analysis showed that no normal, stable allele contained more than 27 uninterrupted GAA triplets. All longer normal alleles were interrupted by a hexanucleotide repeat (GAGGAA). An allele containing an uninterrupted run of 34 GAA triplets was stably transmitted in four instances, but in one case underwent hyperexpansion to 650 triplets. Overall, our results suggest that the FRDA-associated expanded GAA repeats originate from normal alleles by recurrent expansions of alleles at risk.
authors.affiliation: Centre de Recherche Louis-Charles Simard, Montreal, Quebec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Montermini
authors.forename: E
authors.initials: E
authors.lastname: Andermann
authors.forename: M
authors.initials: M
authors.lastname: Labuda
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: M
authors.initials: M
authors.lastname: Pandolfo
authors.forename: F
authors.initials: F
authors.lastname: Cavalcanti
authors.forename: L
authors.initials: L
authors.lastname: Pianese
authors.forename: L
authors.initials: L
authors.lastname: Iodice
authors.forename: G
authors.initials: G
authors.lastname: Farina
authors.forename: A
authors.initials: A
authors.lastname: Monticelli
authors.forename: M
authors.initials: M
authors.lastname: Turano
authors.forename: A
authors.initials: A
authors.lastname: Filla
authors.forename: G
authors.initials: G
authors.lastname: De Michele
authors.forename: S
authors.initials: S
authors.lastname: Cocozza
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004247:DNA; D005621:Friedreich Ataxia / Q000235:genetics*; D006801:Humans; D033862:Iron-Binding Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011110:Polymorphism, Genetic; D018911:Trinucleotide Repeats; D000096923:Frataxin
chemical_list: D004247:DNA; D033862:Iron-Binding Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D000096923:Frataxin