Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia

The Fragile X-associated disorders (FXDs) and Friedreich ataxia (FRDA) are genetic conditions resulting from expansion of a trinucleotide repeat in a region of the affected gene that is transcribed but not translated. In the case of the FXDs, pathology results from expansion of CGG•CCG-repeat tract in the 5′ UTR of the FMR1 gene, while pathology in FRDA results from expansion of a GAA•TTC-repeat in intron 1 of the FXN gene. Expansion occurs during gametogenesis or early embryogenesis by a mechanism that is not well understood. Associated Expansion then produces disease pathology in various ways that are not completely understood either. In the case of the FXDs, alleles with 55–200 repeats express higher than normal levels of a transcript that is thought to be toxic, while alleles with > 200 repeats are silenced. In addition, alleles with > 200 repeats are associated with a cytogenetic abnormality known as a fragile site, which is apparent as a constriction or gap in the chromatin that is seen when cells are grown in presence of inhibitors of thymidylate synthase. FRDA alleles show a deficit of the FXN transcript. This review will address the role of repeat-mediated chromatin changes in these aspects of FXD and FRDA disease pathology. This article is part of a Special Issue entitled: Chromatin in time and space.

► The Fragile X disorders and Friedreich ataxia result from expansion of a tandem repeat tract. ► In all of these diseases the repeat is transcribed but not translated. ► Evidence suggests that repeat-mediated chromatin changes are responsible for disease pathology.