Official websites use. Share sensitive information only on official, secure websites. To whom reprint requests should be addressed. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA.
Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. Indeed, we found two such alleles 42 and 60 GAA that underwent cataclysmic expansion to pathological range in a single generation.
This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences. We identified recently by positional cloning the defective gene, named frataxin, that encodes a protein of unknown function 6.
Pathological alleles were shown to have repeats 6 β 8. The disease is caused by a loss of function of the frataxin protein, as shown by reduction of mRNA level in lymphoblastoid cell lines of patients, and in few cases by point mutations leading to a truncated protein 6. The fragile X syndrome and myotonic dystrophy are also due to large expansions of trinucleotide repeats.
They are characterized by the existence of unstable alleles named premutations in fragile X syndrome that have no pathologic effect but that may lead in one or two generations to the disease-causing alleles 9. Furthermore, in these diseases, linkage disequilibrium between disease alleles and flanking markers results from ancestral events that create normal alleles predisposed to mutate, over many generations, to truly unstable alleles 10 , We wanted to see if similar mechanisms occurred in FRDA.
