Résumé :
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Communication n° 254 Spinal Muscular Atrophy (SMA) is a frequent autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons and caused by mutations of the SMN gene. SMN is thought to be involved in RNA metabolism. However, the pathway linking SMN defect to SMA phenotype remains to be elucidated. Homozygous deletion of murine Smn exon 7 directed to neurons or skeletal muscle causes severe motor axonal or myofiber degeneration, respectively (Frugier et al., 2000; Cifuentes-Diaz et al. 2001 and 2002). cDNA microarrays were used to compare expression profiles of 8400 genes in mutant spinal cord and skeletal muscle before and after the onset of SMA symptoms. Microarray data were validated using real time PCR analysis (89% correlation). We identified a probe set of 429 regulated genes in SMA. Although less than 3% of genes were shared between mutant skeletal muscle and spinal cord, characterization of functional classes of gene products revealed similar proportion of genes involved in cell signalling, cytoskeleton, metabolism and protein degradation. A high proportion of genes (20 out of 429, 5%) were involved in pre-mRNA splicing, ribosomal RNA processing or RNA decay. By analysing other neuromuscular disorders, we determined that most of them (14 out of 18) were specific to SMN defect. In addition, real time PCR analysis showed that activation of these genes was an early adaptive response to lack of full length SMN (FL-SMN), a feature consistent with the role of SMN in RNA metabolism. In human SMA tissues, activation of this process was not observed which could be explained by the residual amount of FL-SMN encoded by the SMN2 gene that remains present in SMA patients. These data raise the question of whether defect of RNA metabolism is involved in human SMA pathogenesis.
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