Résumé :
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Myofibrillar myopathies (MFM) are rare inherited neuromuscular disorders characterized by adult onset and the accumulation of aggregates containing desmin in cardiac and/or skeletal muscle cells. MFM patients present clinical and genetic heterogeneous patterns. In fact, mutations in several genes, such as desmin, have been involved in this pathology. Desmin belongs to the type III intermediate filament (IF) family and is specifically expressed in all muscles. Its main role is maintaining the functional and structural integrity of myofibrils (Li et al, 1997). Our laboratory has been interested for a long time by understanding molecular mechanisms implied in these diseases and by functional consequences for muscle cells. So, we have identified new mutations in desmin gene : some in the alpha helical central domain, and others in non-helical N- and C-ter extremities. Mutations of the rod domain mainly affect regions necessary to network assembly (Goudeau et al 2006), while mutations in N- and C-ter extremities mostly concern putative phosphorylable sites and/or are included in conserved domains of intermediate filament family (Bar et al, 2007). We demonstrated that in contrast to mutants in rod domain, which have a dominant-negative effect, N- and C-ter mutants can self-assemble and form a proper desmin network when they are expressed in different cell lines. These new mechanisms may involve specific protein-protein interactions modulated in part by phosphorylation that we will further investigate. - Li ZL.et al. Desmin is essential for the tensile strength and integrity of myofibrils but not for myogenic commitment, differentiation and fusion of skeletal muscle. 1997 J.Cell.Biol., 139 : 129-44. - Goudeau B et al. Variable pathogenic potentials of mutations located in the desmin alpha helical domain 2006 Hum.Mut. 27 : 906-13. - Bar H. et al. Conspicuous involvment of desmin tail mutations in diverse cardiac and skeletal myopathies 2007 Hum.Mut. 28 : 374-386.
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