The friedreich ataxia GAA triplet repeat: Premutation and normal alleles

被引:166
作者
Montermini, L
Andermann, E
Labuda, M
Richter, A
Pandolfo, M
Cavalcanti, F
Pianese, L
Iodice, L
Farina, G
Monticelli, A
Turano, M
Filla, A
DeMichele, G
Cocozza, S
机构
[1] CTR RECH LOUIS CHARLES SIMARD,MONTREAL,PQ H2L 4M1,CANADA
[2] MONTREAL NEUROL HOSP & INST,MONTREAL,PQ H3A 2B4,CANADA
[3] MCGILL UNIV,DEPT NEUROL,MONTREAL,PQ H3A 2T5,CANADA
[4] MCGILL UNIV,DEPT NEUROSURG,MONTREAL,PQ H3A 2T5,CANADA
[5] MCGILL UNIV,DEPT HUMAN GENET,MONTREAL,PQ H3A 2T5,CANADA
[6] HOP ST JUSTINE,SERV GENET MED,MONTREAL,PQ H3T 1C5,CANADA
[7] UNIV MONTREAL,DEPT MED,MONTREAL,PQ H3C 3J7,CANADA
[8] UNIV NAPLES,DEPT NEUROL,I-80131 NAPLES,ITALY
[9] UNIV NAPLES,DEPT MOL & CELLULAR BIOL,I-80131 NAPLES,ITALY
[10] UNIV NAPLES,DEPT PATHOL,I-80131 NAPLES,ITALY
[11] UNIV NAPLES,CEOS,I-80131 NAPLES,ITALY
关键词
D O I
10.1093/hmg/6.8.1261
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:1261 / 1266
页数:6
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