Résumé :
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Mutations in GNE cause Hereditary Inclusion Body Myopathy (HIBM), an adult onset, slowly progressive distal and proximal myopathy. GNE is well known as the key enzyme for the biosynthesis of sialic acid, but the exact mechanism of the disease is still an enigma. GNE knock out results in embryonal lethality of mice at day E8.5. We have generated a knock in mouse by introducing the founder mutation in Middle Eastern HIBM patients, M712T, by homologous recombination. Mice homozygous for the M712T GNE mutation display an early renal disorder: fatal impairment of glomerular function, and die within few days of birth (consistent with previous data, Galeano et al. 2007). However we encountered phenotypic variability: some animals have a milder phenotype and survive up to 6-8 weeks, and surprisingly few continue to develop as fertile adults. Since HIBM is a late onset disease in humans, we reasoned that the adult mice who presented no apparent kidney phenotype could develop an HIBM like myopathy later in life. Offsprings of crosses among adult homozygous mice showed progressive improvement in survival rate, up to 4 generations (50% survival), but to date, no histological HIBM characteristics or muscle weakness were detected in these mice, (now 20 months old). This phenomenon indicates that GNE's altered function can differentially affect different species, and raises the question whether the different pathology observed between human and mouse as a result of the M712T mutation can be explained by the same mechanism (sialylation defect). The 'saved' phenotype (no myopathy) may indicate a resolution of another pathogenic mechanism.
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