Résumé :
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Schwartz-Jampel syndrome (SJS) is a recessive disorder with neuromyotonia and chondrodysplasia that appear during childhood and slowly progress until adulthood. SJS results from hypomorphic mutations in the perlecan gene, a proteoglycan secreted within basement membranes, and is allelic to DDSH, a recessive chondrodysplasia lethal at birth. A gene dosage effect is currently proposed to account for the difference in severity: the residual level of perlecan secreted in SJS would rescue the lethality due to the complete lack of perlecan in DDSH. To test this hypothesis and understand the pathophysiology of SJS, we developed one mouse model by introducing the p.C1532Y missense mutation into the perlecan gene by homologous recombination. We developed two mouse lines: one (Neo+) still contained the Neo box in addition to p.C1532Y, and the second (Neo-) contained only the p.C1532Y mutation. Homozygous mutant mice from the two lines were viable. A reduced secretion of perlecan was seen in the Neo+ and Neo- mutants, with a lower level in Neo+ compared to Neo- due to splicing events between the perlecan gene and Neo. In the two lines, the adult mutants were smaller than controls and develop a neuromuscular phenotype with delayed opening of the eyelids and flexion of the hind paw when suspended by the tail. Alterations of neuromuscular junctions with lack of pretzel-like shape and acetylcholinesterase deficiency, and histological changes of skeletal muscles similar to those observed in patients with SJS were observed in the two lines, but they were more severe in Neo+. Altogether, our results argue for an inverse correlation between the level of secreted perlecan and the severity of the phenotype, and propose increasing the level of secreted perlecan by acting on the hypomorph effect of the SJS mutations as a rational therapeutic strategy for SJS.
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