title: Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia.
abstract: 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.
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA.
authors.forename: Daman
authors.initials: D
authors.lastname: Kumari
authors.forename: Rachel
authors.initials: R
authors.lastname: Lokanga
authors.forename: Dmitry
authors.initials: D
authors.lastname: Yudkin
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Zhao
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002873:Chromosome Fragility; D042622:DNA Repeat Expansion; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D020080:Tandem Repeat Sequences
chemical_list: D002843:Chromatin; D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human