Résumé :
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Spinal muscular atrophy (SMA) is caused by Survival Motor Neuron (SMN) protein deficiency. The vast majority of SMA patients have deletions of the SMN1 gene, leaving SMN2 as the only source of SMN protein. However, due to a single nucleotide change in SMN2 most (~80%) of the mRNA produced from it is exon 7-skipped and its protein product, SMN7, is highly unstable, resulting in SMN deficiency. SMN is expressed in and essential for all eukaryotic cells but the residual amount of SMN produced from SMN2 is insufficient for motor neurons. SMN is part of a large multi-protein complex (SMN and the Gemins) that plays a central role in cellular RNA metabolism. The SMN complex functions as a molecular assembly machine for snRNPs (small nuclear ribonucleoproteins), which are essential for mRNA biogenesis (splicing and transcriptome protection). Indeed, SMN-deficient SMA patient cells and SMA mouse model have a corresponding deficit in the capacity for snRNP biogenesis. We have shown that this deficiency causes tissue-specific changes in snRNPs and in the transcriptome, including numerous splicing abnormalities. The specific abnormalities in the mRNAs that occur in motor neurons and other cells in pre-symptomatic SMA mice are being studied. Insights from these and from studies of the function and regulation of the SMN complex are being used for high throughput screens to discover potential therapeutics for SMA. We have also recently identified the cause of SMN7 instability and this provides an additional target for SMA therapy. Recent advances from this work will be described.
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