Résumé :
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Spinal muscular atrophies (SMA) are characterized by the degeneration of lower motor neurons, leading to progressive motor paralysis associated with muscular atrophy. SMA is a frequent recessive autosomal disorder caused by mutations of the survival of motor neuron gene (SMN1). SMN1 is duplicated in a highly homologous gene but partly functional, SMN2. Upregulation of the SMN2 gene or preventing exon 7 skipping specific to the SMN2 transcripts have been selected as therapeutic strategies in SMA. Improving the stability of the SMN7 protein, the major product of SMN2, is also regarded as an attractive one. Alternatively or in combination with the above strategy, neuroprotective or neurotrophic factors may protect neurons from degeneration. Several candidate treatment agents are in various stages of development. SMN is involved in, and facilitates, cytoplasmic assembly of snRNP into the spliceosome, a large RNA-protein complex that catalyzes the splicing reaction. The link between RNA metabolism and SMA pathogenesis has been also strongly suggested but the molecular link remains unclear. In order to identify putative targets of the RNA processing defect in SMA and to refine the molecular pathway involved in motor neuron survival in human, a genetic approach has been undertaken aiming at identifying gene(s) responsible for adult onset SMA unlinked to SMN 1, syndromic SMA and sporadic amyotrophic lateral sclerosis. The recent development of robust, high-throughput SNP genotyping and CNV arrays combined with whole exome analysis has been applied and facilitated the identification of new highly candidate loci.
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