Résumé :
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The LMNA gene encodes lamins A and C, two intermediate filament type proteins that are important determinants of interphase nuclear architecture as they play essential roles in maintaining the integrity of the nuclear envelope and chromatin structure. Mutations in the human lamin A/C gene (LMNA) lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreyfuss muscular dystrophy (AD-EDMD) which affects skeletal and cardiac muscle. The cellular mechanism by which mutations in genes encoding nuclear envelope proteins cause striated muscle abnormalities in EDMD has been elusive. LMNAH222P/H222P and LMNA-/- mice develop severe muscle wasting, highly reminiscent of human EDMD and have been used as EDMD animal models. Here we show that these mice fail to innervate muscle and exhibit aberrant neuromuscular junctions (NMJ). In both mice models, several nuclear envelope components crucial for proper recruitment and positioning of synaptic nuclei are mislocalized, leading to a reduction in their number and their mispositioning at the NMJ. Consequently, LMNAH222P/H222P and LMNA-/- muscles show several signs of functional denervation including mis-expression of neurotransmission-defect marker genes and altered epigenetic chromatin modifications. These defects are due to loss of interaction between lamin A and inner nuclear membrane proteins since muscle defects are recapitulated upon transient knockdown of LMNA or expression of a dominant negative form of a lamin A interacting protein. Failed innervation is also a hallmark of biopsies from EDMD patients suggesting these defects are relevant to human disease. These results strongly suggest that lamin A/C mediated neuromuscular junction defects are largely responsible for the disease phenotype in EDMD and they provide the first insights into the cellular and molecular mechanisms for the muscle-specific phenotype of EDMD.
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