Résumé :
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Facioscapulohumeral muscular dystrophy (FSHD) is considered a disorder of gene regulation. The pathological deletions contract the D4Z4 repeat array in the 4q35 subtelomeric region from 11 -150 units in healthy individuals down to 1-10 units in patients. Our group has identified the Double Homeobox 4 (DUX4) gene within the D4Z4 repeat unit, and showed the encoded protein was a potent transcription factor. DUX4 gene expression was detected in FSHD but not control primary myoblasts at both mRNA and protein levels. DUX4 over-expression induced cell death (collaboration with Dr. A. Rosa, INIMEC-CONICET,Cordoba, Argentina). In another study Dr. Y.W. Chen (CNMC, Washington DC, USA) detected a specific 10-15 fold up-regulation of the PITX1 gene (Paired-like homeodomain transcription factor 1) in affected and non-affected muscles of patients with FSHD as compared to 11 other neuromuscular disorders. Interestingly, Pitx1 induces skeletal muscle atrophy in a transgenic mouse model. The question was how a genetic defect in 4q35 could activate the PITX1 gene on chromosome 5. A collaborative study with Dr. Chen showed that the DUX4 protein could specifically bind to the PITX1 promoter and activate its transcription. Both proteins were detected by immunofluorescence in nuclei of FSHD myotubes grown in vitro. These data demonstrated that DUX4 and PITX1 were involved early in the disease: their combined transcriptional activities could disturb expression of a large gene collection. We have also characterized the homologous DUX4c gene centromeric of the D4Z4 array, and showed its expression in controls, and its induction in FSHD and DMD muscle biopsies. DUX4c over-expression induced MYF5 and cell proliferation, and inhibited differentiation to myotubes. These features suggested a role in muscle regeneration that could be disturbed by either DUX4c gene activation or deletion. We will discuss how regulating DUX4, PITX1, and DUX4c expression might constitute therapeutic approaches in FSHD.
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