Background: The Repeat Expansion Diseases are caused by the intergenerational expansion of a specific tandem repeat. GAA.TTC-repeat expansion in the first intron of the frataxin gene results in a transcription defect that leads to a deficit of frataxin, a protein involved in mitochondrial iron homeostasis. This results in Friedreich ataxia (FRDA), a relentlessly progressive neurodegenerative disease. In addition to the consequences of cerebellar degeneration, FRDA symptoms include diabetes and a frequently fatal hypertrophic cardiomyopathy. Thus the frataxin deficit has consequences outside of the CNS as well. How an intronic repeat affects gene expression is unknown. Previous work from our group and others showed that during transcription in vitro the repeat was able to form a triple-stranded DNA structure (triplex) that trapped the RNA polymerase on the template and reduced the overall yield of transcript (Grabczyk and Usdin, 2000 a,b). However, whether such a triplex forms in the endogenous frataxin locus in vivo is unknown. Progress report: We have previously shown that the GAA.TTC-repeat expansion responsible for FRDA causes the locus to become heterochromatinized (Greene et. al., 2007). We have identified both an unusual pattern of aberrant DNA methylation that is superimposed on the basal methylation found in this region even in unaffected individuals. We have also identified a number of key histone modifications that characterize silenced alleles. We are in the process of identifying compounds that are able to successfully reverse the key histone modifications responsible for silencing. To date we have identified one such compound and are currently trying to understand the mechanism involved and its therapeutic potential.

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Kumari, Daman; Usdin, Karen (2012) Is Friedreich ataxia an epigenetic disorder? Clin Epigenetics 4:2
Kumari, Daman; Lokanga, Rachel; Yudkin, Dmitry et al. (2012) Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia. Biochim Biophys Acta 1819:802-10
Kumari, Daman; Biacsi, Rea Erika; Usdin, Karen (2011) Repeat expansion affects both transcription initiation and elongation in friedreich ataxia cells. J Biol Chem 286:4209-15