Résumé :
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Congenital myasthenic syndromes (CMS) are rare hereditary diseases characterized by a dysfunction of the neuromuscular transmission. Our group has identified MUSK mutations (one nonsense and one missense) in a CMS patient. Study of the patient’s muscle biopsy shows inter alia a sprouting of the axonal endings. The over-expression of the missense mutation in mouse skeletal muscle causes an axonal outgrowth at the neuromuscular junction, similar to that observed in the patient. We established that the MuSK mutation expressed by cultured muscle cells was responsible for the release in their medium of a soluble growth factor increasing the axonal growth of cultured motoneurons. We used 2D gel electrophoresis followed by mass spectrometry for characterizing this factor. We identified, among thirty differentially expressed proteins, a fragment of a heparan sulfate proteoglycan, the perlecan. We have controlled the protein potency on axonal growth by carrying out blocking experiments using anti-perlecan antibodies. We proposed that this axonal growth might be favourable to the patient condition and had to be accompanied by the formation of new neuromuscular junctions. Indeed, we noticed an increased number of neuromuscular contacts both in nerve-muscle cocultures and in the KI mouse bearing the MuSK missense mutation. It is conceivable that the motoneurone, previously conditioned by perlecan or another muscle factor, could in turn release a factor, likely agrin, able to aggregate or increase the transcription of acetylcholine receptors. In summary, a mutation of a synaptic muscle protein leads to the discovery of a growth factor, perlecan or one of its fragments. This factor by inducing an axonal sprouting would induce the formation of new neuromuscular junctions in a CMS patient and compensate for the defective synaptic transmission. Supported by APHP, Inserm, ANR Maladies Rares, CMCU and AFM.
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