Résumé :
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Congenital myasthenic syndromes (CMS) correspond to a class of human pathologies resulting from mutations in genes expressed at the neuromuscular junction (NMJ). These disorders are characterized by a dysfunction of the NMJ leading to muscle weakness and excess fatigability (1). One of the CMS is caused by the absence or the poor expression of acetylcholinesterase (AChE) in the synaptic basal lamina and is referred as CMS-1c. The first symptoms for this pathology are detected in the neonatal period or the childhood and most of the patients are severely disabled. For the majority of the patients, the clinical picture includes muscle hypotonia, ptosis, respiratory insufficiency and delayed motor development (2). The syndrome is not due to mutations in the ACHE gene but to mutations in COLQ, a gene that encodes a specific collagen anchoring AChE in NMJ (3). Several partners of ColQ have been identified including perlecan (4) and indirectly dystroglycan (DG), a transmembrane protein that links the extracellular matrix to the cytoskeleton (5). We also showed that the C-terminus of ColQ binds MuSK, a key organizer of the NMJ (6). A mouse model of CMS-1c has been generated by invalidation of the COLQ gene (7). As recently shown using the ColQ-deficient mice, ColQ participates in postsynaptic differentiation by regulating the density of AChR and the size of the synaptic clusters (8). Here, we have conducted a large genetic screen to identify the molecular targets of ColQ and revealed molecular defects that could explain the observed phenotype in the mice model of CMS-1c. The results point to two main consequences of the deficit in ColQ, a synaptic atrophy that could be linked to the MuSK pathway and an upregulation of a subset of synaptic genes. We will discuss the consequences of these molecular and cellular hallmarks for the physiopathology of the neuromuscular junction.1. Hantai, D., Richard, P., Koenig, J., and Eymard, B. (2004) Curr Opin Neurol 17, 539-5512. Mihaylova, V. et al. (2008) Brain 131, 747-7593. Krejci, E., Thomine, S., Boschetti, N., Legay, C., Sketelj, J., and Massoulie, J. (1997) J Biol Chem 272, 22840-228474. Arikawa-Hirasawa, E., Rossi, S. G., Rotundo, R. L., and Yamada, Y. (2002) Nat Neurosci 5, 119-1235. Jacobson, C., Cote, P. D., Rossi, S. G., Rotundo, R. L., and Carbonetto, S. (2001) J Cell Biol 152, 435-4506. Cartaud, A., Strochlic, L., Guerra, M., Blanchard, B., Lambergeon, M., Krejci, E., Cartaud, J., and Legay, C. (2004) J Cell Biol 165, 505-5157. Feng, G., Krejci, E., Molgo, J., Cunningham, J. M., Massoulie, J., and Sanes, J. R. (1999) J Cell Biol 144, 1349-13608. Sigoillot, S. M., Bourgeois, F., Lambergeon, M., Strochlic, L., and Legay, C. (2010) J Neurosci 30, 13-23
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