Résumé :
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Congenital Myasthenic Syndromes (CMS) are inherited muscular disorders affecting neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (ColQ) underlie synaptic basal lamina associated congenital myasthenia with end-plate AChE deficiency (CMS-1C). Until now, most of the defects observed in patients with CMS due to mutations in ColQ have been interpreted in the light of the absence of AChE. However, considering currently known ColQ interactions in the basal lamina of the neuromuscular junction (NMJ) with MuSK (Muscle Specific Kinase) and Perlecan, we made the hypothesis that ColQ could control per se postsynaptic development and organization independently of AChE. MuSK is a signalling platform implicated in the transcription and accumulation of acetylcholine receptors (AChR). The heparan sulfate proteoglycan Perlecan binds to Dystroglycan (DG) known to be crucial for synapse differentiation and muscle integrity. To study ColQ effects on these two signalling pathways, a wt and a ColQ deficient (ColQ-/-) cell lines were compared using various techniques such as microarrays, classic RT-PCR and TaqMan Low Density Arrays (TLDA), western blotting and immunofluorescence. We show that the absence of ColQ leads to a disorganization of the extracellular matrix that could lead to defects in muscle cell differentiation as well as in synaptic protein expression. In particular, the absence of ColQ upregulates AChR expression and proteins involved in AChR aggregation but downregulates proteins involved in AChR cluster stabilization. Since ColQ controls AChR expression, it suggests that there is an adaptive mechanism linking AChE levels to those of AChR. In addition, pathological effects could be the results of DG low expression and low stimulation by Perlecan and Laminin, both of which are downregulated in ColQ-/- cells. Thus, CMS-1C would not be only due to the absence of AChE in basal lamina, but probably also linked to developmental disorders with maturation defects.
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