title: 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.
abstract: 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.
authors: Inserm U614, IFRMP, Institute for Biomedical Research, University of Rouen, 76183 Rouen, France.
authors: Myriam
authors: M
authors: Vezain
authors: Pascale
authors: P
authors: Saugier-Veber
authors: Elisa
authors: E
authors: Goina
authors: Renaud
authors: R
authors: Touraine
authors: Véronique
authors: V
authors: Manel
authors: Annick
authors: A
authors: Toutain
authors: Séverine
authors: S
authors: Fehrenbach
authors: Thierry
authors: T
authors: Frébourg
authors: Franco
authors: F
authors: Pagani
authors: Mario
authors: M
authors: Tosi
authors: Alexandra
authors: A
authors: Martins
mesh_terms: D000293:Adolescent; D000328:Adult; D001665:Binding Sites; D002675:Child, Preschool; D004742:Enhancer Elements, Genetic; D005091:Exons; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*
chemical_list: D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; D055540:Survival of Motor Neuron 2 Protein