Abstract
Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder commonly caused by large expansions of a GAA repeat in the first intron of the frataxin gene, FRDA. The expansion of the triplet repeat is localized within an Alu sequence. FRDA GAA-repeat alleles can be divided into three classes depending on their lengths: short normal alleles (SN), long normal alleles (LN) and expanded pathological alleles (E). We made an accurate analysis of the Alu sequence containing the GAA repeat. We found a new single-nucleotide polymorphism (SNP) that is the closest one to the GAA repeat. We studied this new SNP and the polymorphic polyA region contiguous to the GAA triplets in two populations with different frequencies of FRDA. We found that, while both E and LN alleles seem to be genetically homogeneous and likely related, SN represents a more heterogeneous class of alleles. Indeed, one SNP variation (T) was more frequently associated with (GAA)8 alleles, whereas the other one (C) with (GAA)9 repeat(s). The long normal and expanded alleles presented the C haplotype. The same correlation was described for polyA-tract polymorphisms. Thus, 14A was commonly associated with (GAA)8 alleles and 17A with (GAA)9 alleles. The long normal alleles more frequently showed the 17A haplotype. Our data seem to suggest that all the E alleles come from LN alleles, while LN alleles come from a defined subclass of SN alleles.
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Monticelli, A., Giacchetti, M., De Biase, I. et al. New clues on the origin of the Friedreich ataxia expanded alleles from the analysis of new polymorphisms closely linked to the mutation. Hum Genet 114, 458–463 (2004). https://doi.org/10.1007/s00439-004-1089-7
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DOI: https://doi.org/10.1007/s00439-004-1089-7