Résumé :
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Communication n° 286 Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an expansion of CTG repeats in the 3'UTR of the DMPK gene. Major clinical features are myotonia, muscle weakness, cardiac arrhythmia, insulin resistance, and cognitive impairment. This multisystemic pathology may be due to an aberrant alternative splicing of multiple RNAs in several organs: ClC-1, Insulin Receptor (IR), myotubularin in muscles and cTNT in heart. More recently, our group also demonstrated a defect in Tau exon 2 and 3 alternative splicing in DM1 brain. As the alternative splicing may be tissue-regulated, DM1 raises the question of a possible common mechanism of alternative splicing dysregulation in different organs. To address this question, we decided to study Tau alternative splicing in DM1. Indeed, it is well known that Tau exons 2, 3 and 6 are alternatively spliced in brain and muscle. We showed that aberrant alternative splicing of exons 2 and 3 of Tau occurred not only in DM1 brain but also into DM1 muscle. For the first time, a defect in alternative splicing of Tau exon 6 was observed in DM1 brain. In fact, the existence of three distinct 3'splicing sites leads to the inclusion of 3 possible cassettes: exon 6c, 6p or 6d. In DM1 brain, exon 6c inclusion decreased while exons 6p and 6d increased slightly. Interestingly, no aberrant alternative splicing of exon 6 occurred in DM1 muscle. This alteration seemed then to be brain specific in contrast to exons 2 and 3. Finally, cell transfections with ETR-3 cDNA, a splicing factor, decreased the inclusion of endogenous Tau exons 2 and 3 but not 6c but also inclusion of endogenous IR exon 11 therefore reproducing a DM1-muscle pattern. Altogether, these results suggest that the different splicing dysregulations observed in DM1 did not result from an unique process and would involve different splicing factors according to the altered exon and tissue. One of these factors could be ETR-3. Acknowledgement to AFM for financial support.
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