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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
Author(s) -
Vezain Myriam,
SaugierVeber Pascale,
Goina Elisa,
Touraine Renaud,
Manel Véronique,
Toutain Annick,
Fehrenbach Séverine,
Frébourg Thierry,
Pagani Franco,
Tosi Mario,
Martins Alexandra
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21173
Subject(s) - exon , spinal muscular atrophy , rna splicing , alternative splicing , medicine , atrophy , exonic splicing enhancer , anatomy , biology , genetics , pathology , gene , rna
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 HTra2â 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.