Résumé :
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Neuromuscular disorders represent a relatively heterogeneous group of diseases affecting muscle function either directly (myopathies), or indirectly via nerve (neuropathies) or neuromuscular junction dysfunctions. Peripheral neuropathies, which affect either neurons (axonopathies) or Schwann cells (myelopathies), lead in the majority of cases to impaired muscular function.Charcot-Marie-Tooth 4C (CMT4C) is a demyelinating autosomal recessive neuropathy leading to delayed age of walking, muscular atrophy, weakness, reduced muscle tone, early onset severe scoliosis, areflexia, sensory impairment, foot deformities and reduced motor and sensory nerve conduction velocities. The identification of SH3TC2, the gene mutated in CMT4C patients (Senderek et al., 2003) allowed recent re-evaluation of different cohorts of patients with unexplained autosomal recessive (AR) CMT and led to the discovery that a mutation in SH3TC2 is the most frequent cause of AR-CMTs. These discoveries therefore had an immediate impact on genetic diagnostics and counseling of CMT patients. However, the molecular role that SH3TC2 plays in the peripheral nervous system (PNS) remains to be clarified. In order to characterize its function in vivo, we have recently generated Sh3tc2-knockout mice (Arnaud et al. 2009). Similarly to the phenotype described in CMT4C patients, we have also observed hypomyelination in the PNS. Interestingly, investigation of the structure of the nodes of Ranvier in the PNS of these mice has highlighted a previously undetected wider nodal space. Importantly, we were able to confirm the presence of this phenotype in sural nerve biopsies from CMT4C patients.The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.
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