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

作者：Vezain Myriam; Saugier Veber Pascale; Goina Elisa; Touraine Renaud; Manel Veronique; Toutain Annick; Fehrenbach Severine; Frebourg Thierry; Pagani Franco; Tosi Mario; Martins Alexandra^*

来源：Human Mutation, 2010, 31(1): E1110-E1125.

DOI：10.1002/humu.21173

• Spinal Muscular Atrophy
• Splicing regulatory element
• Genetic modifier
• hnRNP A1

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 HTra2 beta 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.

• 出版日期2010-1