Friedreich ataxia is an autosomal recessive disease, characterized clinically by ataxia (incoordination), cardiomyopathy and diabetes. The most common mutation, seen in >95% of patients is an abnormal expansion of a GAA triplet-repeat sequence in intron 1 of the FRDA (frataxin) gene. Normal and mutant alleles contain 6 - 100 and 100 - 1700 triplets, respectively. Expanded (mutant) alleles exhibit marked instability in somatic cells and during intergenerational transmission. Disease-causing expansions arise when premutation alleles (30 - 100 triplets) undergo hyperexpansion during intergenerational transmission. The mechanism of hyperexpansion of premutation alleles and the subsequent somatic and germline instability of expanded alleles remains poorly understood. The overall goal of this project is to investigate the mutagenic mechanisms underlying the genetic instability of the GAA triplet-repeat sequence. We will perform """"""""small-pool PCR"""""""" (SP-PCR) analysis to test the pattern of genetic instability of normal, premutation, and expanded chromosomes, in a wide variety of somatic tissues and germ cells derived from patients and asymptomatic carriers of various alleles. We will investigate the effect of DNA replication on GAA triplet-repeat instability using a defined eukaryotic replication model system. We will also investigate the role of cis-acting and epigenetic modifiers in determining instability of the GAA triplet-repeat sequence. It is hoped that these studies will lead to the development of novel strategies to prevent or reverse the process of GAA triplet-repeat expansion as a possible future therapy for Friedreich ataxia. Our data could potentially lead to the discovery of general properties of triplet-repeat instability, which will have implications for other diseases caused by this mutational mechanism.
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