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

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• 作者：Daman Kumari¹ ; Rachel Lokanga¹ ; Dmitry Yudkin¹ ; Xiao-Nan Zhao¹ ; Karen Usdin ; ^{ku@helix.nih.gov}
• 关键词：FM ; full mutation ; FRDA ; Friedreich ataxia ; FS ; fragile site ; FXDs ; Fragile X associated disorders ; FXPOI ; Fragile X-associated primary ovarian insufficiency ; FXTAS ; Fragile X-associated tremor and ataxia syndrome ; FXS ; Fragile X syndrome ; PM ; premutation
• 刊名：Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
• 出版年：2012
• 期刊代码：P11_18749399
• 类别：bio
• 出版时间：July, 2012
• 卷：1819
• 期：7
• 页码：802-810
• 文件大小：577 K

摘要

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鈥CG-repeat tract in the 5鈥?UTR of the FMR1 gene, while pathology in FRDA results from expansion of a GAA鈥TC-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.