Résumé :
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Facioscapulohumeral dystrophy (FSHD) is a human myopathy characterized by a progressive decrease in muscle mass and weakness in facial, upper arm, shoulder girdle and lower limb muscles, these symptoms frequently showing a right/left asymmetry. The disease is linked to contractions of the D4Z4 repeats in the 4q35 region of chromosome 4. Interestingly, each D4Z4 repetition contains one single ORF coding for Dux4. But even if it has been showed that Dux4 is expressed in FSHD samples, no direct correlation between Dux4 expression and the disease has been found. The molecular mechanism leading to FSHD still remains to be understood. In a collaborative study involving 3 French laboratories, we have identified a gene down-regulated in FSHD muscle biopsies, and which knock down in mouse causes phenotypes recapitulating all the key features of the FSHD disease: atrophy, muscle specificity, asymmetry and retinal vasculopathy (see Francoise Helmbacher's abstract). Because this gene has never been described to play a role in muscle biology, our goal is to understand its biological function and to analyze how its functions may underlie the onset and progression of the disease. We have cultivated control or FSHD primary cells under proliferating or differentiating conditions, and the mRNA expression level of this gene was investigated. We have observed that the global expression level of the mRNA of this gene is also down regulated in FSHD myoblasts as compared to control myoblasts. Interestingly, its expression is modified in myotubes as compared to myoblasts. This may indicate a possible participation of this gene to the differentiation/fusion process. Moreover, different alternatively spliced transcripts of this gene are present in proliferating or differentiating conditions. These transcripts correspond to the inclusion in or out of frame of small portions of introns leading to either a longer or a truncated protein, possibly modulating the functions and/or sub-cellular localization of the resulting protein. We have analyzed the expression levels of the different transcripts in both proliferation or differentiation conditions in vitro, as well as in FSHD and control biopsies, and the results will be presented during the meeting.We are now investigating the specific function of these transcripts in muscle biology and in FSHD.
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