Résumé :
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Myotonic dystrophy (DM) is the most common form of adult muscular dystrophy, with a worldwide incidence of 1 in 8000. Although traditionally regarded as a muscle disease, DM has also emerged as a brain disorder. DM type 1 (DM1) is caused by the expansion of an unstable trinucleotide CTG repeat in the 3’UTR of the DM protein kinase (DMPK) gene. Repeat length correlates directly with disease severity and inversely with age of onset. Therefore, intergenerational expansion-biased repeat instability provides the molecular explanation for the increasing severity of the symptoms and earlier age of onset in successive generations of an affected family. Experimental evidence supports a trans dominant effect of CUG-containing transcripts: toxic CUG repeats accumulate in nuclear foci, affecting the levels and/or localisation of key splicing regulators, and disrupt the processing of multiple downstream RNA transcripts. We have previously generated transgenic mice to investigate the mechanisms of trinucleotide repeat expansion and the molecular pathogenesis of DM1. DM300 mice carry a highly unstable 300-CTG expansion in the context of the human DM1 locus. These animals recreate important aspects of the disease, including myotonia, myopathy, nuclear RNA foci accumulation in multiple tissues and misdistribution of tau protein isoforms in brain. Large intergenerational expansions or “big jumps” (ranging between 200 and 500 CTG in one single transmission) have been recently reported in DM300 mice, resulting in very large trinucleotide sequences (up to 1800 CTG repeats), reduced body size and splicing abnormalities, notably in muscle and brain. Interestingly, the extent of the splicing defects observed varies between muscles and brain regions. We are currently using our mouse model to investigate the relationship between key splicing factors and abnormal RNA metabolism in DM1. Transgenic mice carrying very large CTG repeat expansions provide a useful tool to dissect the molecular disease pathogenesis and to assess novel therapeutic schemes.
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