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

Hum Mutat. 2010 Jan;31(1):E1110-25. doi: 10.1002/humu.21173.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Binding Sites
  • Child, Preschool
  • Enhancer Elements, Genetic*
  • Exons*
  • Female
  • Gene Dosage
  • Genetic Variation*
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • Humans
  • Male
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / physiopathology*
  • RNA Splicing*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Severity of Illness Index
  • Survival of Motor Neuron 2 Protein / genetics*


  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • RNA, Messenger
  • Survival of Motor Neuron 2 Protein