Résumé :
|
Myotonic dystrophy (DM1) is an autosomal dominant neuromuscular disease caused by an expanded trinucleotide repeat (CTG, n >50) located in the 3’UTR of the DMPK gene. The classic adult form is characterized by myotonia, progressive muscle weakness and wasting and the severe congenital form is associated by impairment in skeletal muscle development. The variable and progressive phenotype observed in DM1 patients is caused by a complex molecular pathogenesis. An increasing body of evidence suggests that the nuclear accumulation as discrete foci of mutant DMPK transcripts containing CUG expansions may contribute to the DM1 physiopathology. MBNL1 proteins bind specifically to these CTG expanded repeats and their normal functions in the regulation of alternative splicing of pre-mRNAs are altered. In addition, the MBNL1 knockout mouse model reproduces RNA splicing abnormalities that are characteristic of DM1 disease suggesting that MBNL1 deregulation plays a role in the development of the pathology. Interestingly, MBNL1 itself is also subject to alternative splicing. In this study we will determine if MBNL1 splicing is altered in the muscle of DM1 patients. We have analysed the expression of the different isoforms of MBNL1 during normal human muscle development and in DM1 patients. Preliminary results will be presented.
|