Résumé :
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Schwartz-Jampel syndrome (SJS) is a recessive disorder characterized by permanent muscle stiffness and spontaneous activity in the rest electromyogram that appears during childhood and slowly progress until adulthood. SJS results from hypomorphic mutations in the perlecan gene, a proteoglycan of basement membranes (BM) involved in cell adhesion, growth factor signaling, and maintenance of BMs. We have developed a mouse model of SJS with reduced levels of perlecan in all neuromuscular BMs and have shown by standard EMG investigations of this model the occurrence of distal peripheral nerve hyperexcitability (PNH) without demyelinating neuropathy in SJS. We have now investigated further the adult SJS mice to gain insight into the pathophysiology of PNH. In humans and mice, PNH occurs in demyelinating peripheral neuropathies or diseases caused by mutations in potassium channels (Kv1.1 and Kv7.2). Therefore, we analyzed the distal region of the nerve fibers, closed to the neuromuscular junctions (NMJ), since this region is known to favor PNH. Electrophysiological analyses of phrenic nerve-diaphragm preparations of SJS mutant mice demonstrated the occurrence of spontaneous activity in the diaphragm not associated with spontaneous activity in the proximal phrenic nerve, suggesting a distal origin for this activity. Morphological analyses of nerve-muscle preparations showed a remodeling of distal myelinating and terminal Schwann cells without evidence for denervation (alphaBGT, NF and S100 co-immunostaining) in mutants compared to controls. MBP immunostaining showed that this remodeling was associated with an increased length of the non-myelinated terminal segment in mutants compared to controls. This last observation suggests the occurrence of distal demyelination of the nerve fibers. This distal demyelination questions the ion channel organization of the terminal nerve fiber segment (terminal heminode and non-myelinated segment in SJS mice, which is currently investigated. Supported by AFM, NeRF, INSERM, CNRS, UPMC, MESR
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