| Rbfox1 Downregulation and Altered Calpain 3 Splicing by FRG1 in a Mouse Model of Facioscapulohumeral Muscular Dystrophy (FSHD). | |
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MedLine Citation:
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PMID: 23300487 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle disease whose molecular pathogenesis remains largely unknown. Over-expression of FSHD region gene 1 (FRG1) in mice, frogs, and worms perturbs muscle development and causes FSHD-like phenotypes. FRG1 has been implicated in splicing, and we asked how splicing might be involved in FSHD by conducting a genome-wide analysis in FRG1 mice. We find that splicing perturbations parallel the responses of different muscles to FRG1 over-expression and disease progression. Interestingly, binding sites for the Rbfox family of splicing factors are over-represented in a subset of FRG1-affected splicing events. Rbfox1 knockdown, over-expression, and RNA-IP confirm that these are direct Rbfox1 targets. We find that FRG1 is associated to the Rbfox1 RNA and decreases its stability. Consistent with this, Rbfox1 expression is down-regulated in mice and cells over-expressing FRG1 as well as in FSHD patients. Among the genes affected is Calpain 3, which is mutated in limb girdle muscular dystrophy, a disease phenotypically similar to FSHD. In FRG1 mice and FSHD patients, the Calpain 3 isoform lacking exon 6 (Capn3 E6-) is increased. Finally, Rbfox1 knockdown and over-expression of Capn3 E6- inhibit muscle differentiation. Collectively, our results suggest that a component of FSHD pathogenesis may arise by over-expression of FRG1, reducing Rbfox1 levels and leading to aberrant expression of an altered Calpain 3 protein through dysregulated splicing. |
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Authors:
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Mariaelena Pistoni; Lily Shiue; Melissa S Cline; Sergia Bortolanza; Maria Victoria Neguembor; Alexandros Xynos; Manuel Ares; Davide Gabellini |
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Publication Detail:
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Type: Journal Article Date: 2013-01-03 |
Journal Detail:
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Title: PLoS genetics Volume: 9 ISSN: 1553-7404 ISO Abbreviation: PLoS Genet. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-09 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101239074 Medline TA: PLoS Genet Country: United States |
Other Details:
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Languages: eng Pagination: e1003186 Citation Subset: IM |
Affiliation:
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Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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