Abstract
Spinal muscular atrophy (SMA) is a recessive disorder involving the loss of motor neurons from the spinal cord. Homozygous absence of the survival of motor neuron 1 gene (SMN1) is the main cause of SMA, but disease severity depends primarily on the number of SMN2 gene copies. SMN protein levels are high in normal spinal cord and much lower in the spinal cord of SMA patients, suggesting neuron-specific regulation for this ubiquitously expressed gene. We isolated genomic DNA from individuals with SMN1 or SMN2 deletions and sequenced 4.6 kb of the 5′ upstream regions of the these. We found that these upstream regions, one of which is telomeric and the other centromeric, were identical. We investigated the early regulation of SMN expression by transiently transfecting mouse embryonic spinal cord and fibroblast primary cultures with three transgenes containing 1.8, 3.2 and 4.6, respectively, of the SMN promoter driving β-galactosidase gene expression. The 4.6 kb construct gave reporter gene expression levels five times higher in neurons than in fibroblasts, due to the combined effects of a general enhancer and a non-neuronal cell silencer. The differential expression observed in neurons and fibroblasts suggests that the SMN genes play a neuron-specific role during development. An understanding of the mechanisms regulating SMN promoter activity may provide new avenues for the treatment of SMA.
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Acknowledgements
We wish to thank Drs Bénedicte Gerard and Suzie Lefebvre for providing DNA samples from patients and comments on the manuscript, Dr Judith Melki for plasmids, Dr Jorge Gallego for help with statistics, Drs Noufissa Oudhiri and Pierre Lehn for the CMVpGL2 construct, and Dr Geneviève Rougon for anti-PSA N-CAM antibodies. We thank the Institut Federatif de Recherche 02 (Faculté X. Bichat, Paris VII, France), Dr Alain Vandewalle and Françoise Cluzeaud (INSERM U478, Paris, France) for assistance with confocal microscopy. This work was supported by a grant from INSERM. BB and CM were supported by Cino del Duca Foundation and France-Telecom Foundation fellowships, respectively.
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Boda, B., Mas, C., Giudicelli, C. et al. Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells. Eur J Hum Genet 12, 729–737 (2004). https://doi.org/10.1038/sj.ejhg.5201217
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DOI: https://doi.org/10.1038/sj.ejhg.5201217
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