Résumé :
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INTRODUCTION : Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disorder affecting 1/8000 individuals worldwide. This disease is caused by an unstable expansion of CTG trinucleotide repeats located in the 3' untranslated region of the dystrophy myotonic protein kinase (DMPK) gene (Fu et al, 1992). In muscle cells, the mutated DMPK transcript is retained in nuclear foci (Davis et al, 1997) where it sequesters the splicing factor MBNL1 (Mankodi et al, 2001). In addition, the activation of the protein kinase C in DM1 muscle cells leads to an increased stability of the splicing factor CUGBP1 (Kuyumcu-Martinez et al, 2007). AIM : Dissecting the role played by each factor (Mbl and/or Bru-3) in the heart of DM1 flies to better understand the origin of cardiac symptoms in patients and their diversity from one patient to another. METHOD : Thanks to site-specific transgenesis, we generated a Drosophila model of DM1 expressing non-coding RNAs with 240, 480, 600 or 960 CUG interrupted repeats. In order to better understand the role played by MBNL1 and CUGBP1 in this disease, 2 lines were tested in parallel with DM1 lines: (i) bru-3 gain-of-function line that mimics CUGBP1 stabilization in muscle cells of DM1 patients (ii) line with attenuated mbl expression that mimics the decreased availability of MBNL1 in muscle cells of DM1 patients. Heart physiology analyses were performed on semi-intact preparation of 1 week-old and 5 week-old flies. RESULTS : Decreasing Mbl in cardioblasts leads to significant increased heart period (both diastolic and systolic intervals increased), increased arrythmia and asystoles associated with dilated cardiomyopathy (increased diastolic and systolic diameters, decreased fractional shortening). Surprisingly, the DM1 line with 960 repeats display fibrillation and/or a 3-step beating phenotype which are both age dependant. Interestingly, these phenotypes are reproduced by the bru-3 gain-of-function line. DISCUSSION -CONCLUSION : DM1 lines and Mbl attenuated line display different cardiac phenotypes which can be both found in DM1 patients. Taken together, our results suggest that Bru-3 is the factor involved in cardiac phenotypes observed in DM1 lines. Thus rescue experiments with a bru-3 deficient line are in progress.
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