A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy
✍ Scribed by Myriam Vezain; Pascale Saugier-Veber; Elisa Goina; Renaud Touraine; Véronique Manel; Annick Toutain; Séverine Fehrenbach; Thierry Frébourg; Franco Pagani; Mario Tosi; Alexandra Martins
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 405 KB
- Volume
- 31
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by homozygous inactivation of the SMN1 (Survival Motor Neuron 1) gene. The disease severity is mainly influenced by the copy number of SMN2, a nearly identical gene from which only low amounts of full-length mRNA are produced. This correlation is not absolute, suggesting the existence of yet unknown factors modulating disease progression. We identified and characterized the rare variant c.859G>C (p.Gly287Arg) in exon 7 in both SMN2 copies of a male patient affected with type III SMA, a milder form of the disease rarely associated with only two SMN2 copies. We demonstrated in vivo, in this patient and in a second unrelated patient, and ex vivo, using SMN splicing assays, that the variant induces inclusion of exon 7 into SMN2 mRNA. Moreover, we show that the c.859G>C variation is located in a composite splicing regulatory element in the centre of exon 7. The variation does not affect binding of HTra2β nor creates a novel SF2/ASF enhancer, but disrupts an hnRNP A1 binding site. The natural occurrence of enhanced inclusion of SMN2 exon 7 in milder SMA cases supports the current therapeutic strategies based on splicing modulation in SMA patients. ©2009 Wiley-Liss, Inc.