Examining the repressive nature of D4Z4 repeats and their role in the pathogenesis of facioscapulohumeral muscular dystrophy.

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Title: Examining the repressive nature of D4Z4 repeats and their role in the pathogenesis of facioscapulohumeral muscular dystrophy.
Authors: Yip, Darren J.
Date: 2002
Abstract: Molecular analysis of Facioscapulohumeral Muscular Dystrophy (FSHD) patients has demonstrated that the disorder is associated with deletions of multiple copies of a subtelomeric 3.3 kb unit termed D4Z4, which lie at 4q35. Sequence analysis of the D4Z4 repeat has failed to identify a functional transcript; thus, it has been postulated that FSHD results from position effects on a neighboring gene(s). The purpose of our investigation was to determine the function that these repeats may hold in the pathogenesis of FSHD by evaluating their regulatory effect on reporter gene expression. To address this, we developed LacZ expression constructs containing 1 to 4 D4Z4 repeats and assessed reporter gene activity using transient and stable transfection assays in C2C12 myoblasts. Our results have revealed inconclusive evidence to support a repressive effect involving the D4Z4 repeats in either transient transfections or stable clones grown under normal or myogenic differentiation conditions. However, during differentiation it was observed that the D4Z4 repeats confer a mild fusion defect onto the multinucleated myofibres. The presence of D4Z4 not only accompanied the reduced fusion competence of myoblast cultures resulting in the formation of less myotubes, but also corresponded to the heightened incidence of deformed myotubes. While the results of these experiments do not provide irrefutable evidence, they have provided some insight towards an association between the D4Z4 repeat and repression and have increased our understanding of the role D4Z4 repeats may play in the etiology of Facioscapulohumeral Muscular Dystrophy.
URL: http://hdl.handle.net/10393/6428
http://dx.doi.org/10.20381/ruor-11269
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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