Document Detail

Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).
MedLine Citation:
PMID:  23300487     Owner:  NLM     Status:  MEDLINE    
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.
Mariaelena Pistoni; Lily Shiue; Melissa S Cline; Sergia Bortolanza; Maria Victoria Neguembor; Alexandros Xynos; Manuel Ares; Davide Gabellini
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-03
Journal Detail:
Title:  PLoS genetics     Volume:  9     ISSN:  1553-7404     ISO Abbreviation:  PLoS Genet.     Publication Date:  2013  
Date Detail:
Created Date:  2013-01-09     Completed Date:  2013-05-30     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  101239074     Medline TA:  PLoS Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1003186     Citation Subset:  IM    
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MeSH Terms
Alternative Splicing / genetics
Calpain* / genetics,  metabolism
Cells, Cultured
Disease Models, Animal
Gene Expression Regulation, Developmental
HEK293 Cells
Muscle Development / genetics
Muscle Proteins* / genetics,  metabolism
Muscular Dystrophy, Facioscapulohumeral* / genetics,  metabolism,  pathology
Myoblasts / cytology,  metabolism
Proteins* / genetics,  metabolism
RNA-Binding Proteins / genetics*,  metabolism
Grant Support
204279//European Research Council; TCR11003//Telethon
Reg. No./Substance:
0/A2BP1 protein, mouse; 0/Frg1 protein, mouse; 0/Muscle Proteins; 0/Proteins; 0/RNA-Binding Proteins; EC 3.4.22.-/Calpain; EC 3.4.22.-/Capn3 protein, mouse

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