Résumé :
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Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder that results in several characteristic symptoms including myotonia, muscle weakness and wasting, pain, cardiac defects, cataracts, cognitive impairments, and endocrine abnormalities. Converging lines of evidence have emerged to support the idea that an abnormal expansion of CUG nucleotide repeats in the 3'UTR of the myotonic dystrophy protein kinase (DMPK) mRNA is the main cause of these complex symptoms. Specifically, it is now believed that mutant DMPK transcripts cause a toxic RNA gain of function as they sequester through their 3’UTR expansion, RNA-binding proteins and transcription factors destined to normally regulate other target mRNAs and/or genes. Accordingly, it has become essential to identify proteins that interact with mutant DMPK transcripts and determine if their pattern of interaction is altered in diseased cells. Staufen is a RNA-binding protein known to be involved in RNA transport. Here, we initiated a series of experiments aimed at determining whether Staufen participates in the complex DM1 pathology. Our results show that levels of Staufen protein are increased in muscles from a DM1 mouse model engineered to express a pathogenic transgene. Using immunoprecipitation analysis, we demonstrate that Staufen binds to DMPK mRNA in skeletal muscle cells. Interestingly, Staufen protein seems also involved in pre-mRNA splicing. As several mRNAs are known to be mis-spliced in DM1, we propose that Staufen may be responsible for some of these defects, and thus could contribute to the basic mechanisms underlying the complex phenotype associated with DM1. This work is supported by the CIHR and AFM.
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