Is Friedreich ataxia an epigenetic disorder?

Clinical Epigenetics 2012, 4:2 doi:10.1186/1868-7083-4-2
Published: 30 January 2012 (OPEN ACCESS)

Daman Kumari and Karen Usdin

Abstract (provisional)

Friedreich ataxia (FRDA) is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat number exceeds a critical threshold. In the case of FRDA, the repeat unit is the triplet GAA*TTC and the tandem array is located in the first intron of the FXN gene. Pathology arises because expanded alleles make lower than normal levels of mature FXN mRNA and thus reduced levels of frataxin, the FXN gene product. The repeats form a variety of unusual DNA structures including triplexes. They also form persistent RNA:DNA hybrids in vitro and in bacteria and affect splicing in model systems. More recently the repeats in the FXN gene have also been shown to be enriched for epigenetic marks that are characteristic of transcriptionally repressed regions of the genome. However, exactly how repeats in an intron cause the FXN mRNA deficit in FRDA has been the subject of much debate. Identifying the mechanism or mechanisms responsible for the FXN mRNA deficit in FRDA is important for the development of treatments for this currently incurable disorder. This review discusses evidence for and against possible models for the repeat-mediated mRNA deficit.

Full text pdf