Résumé :
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Myotonic Dystrophy type 1 (DM1), the most common form of inherited muscular dystrophy in adults, is due to an unstable expansion of CTG triplet repeats in the 3'-untranslated region of the DMPK gene. This generates alternate splicing defects in a large number of genes. The most explored molecular mechanism for those alterations is the abnormal function of the RNA-binding proteins MBNL1, which is sequestered with the mutant RNA in intranuclear inclusions known as "foci" and CUGBP1. We have postulated that other RNA-BPs that would share RNA-binding domains with either one of those two proteins may play a role in the molecular mechanisms related to DM1. We have made use, for that study, of human pluripotent stem cell lines derived from embryos that displayed the mutant DMPK gene, as characterized during pre-implantation genetic diagnosis. Cells of those DM1 lines differentiated along the mesodermal lineage exhibited foci and abnormal splicing of the insulin receptor (INSR) gene, allowing us to challenge 15 different RNA-BPs through a siRNA screen. One of them impacted the ratio of INSR isoforms in a positive way toward normalization while its overexpression conversely exacerbated the splicing defect. By the way, positive effects of the extinction of this gene were mimicked by a chemical molecule regulating its subcellular shuttling. As a similar correction of abnormal splicing was extended to several other gene affected
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