The regulation and regulatory activities of alternative splicing of the SMN gene

Natalia N. Singh, Elliot J. Androphy, Ravindra N. Singh

Research output: Contribution to journalReview articlepeer-review

43 Scopus citations


Alternative splicing is an essential process that produces protein diversity in humans. It is also the cause of many complex diseases. Spinal muscular atrophy (SMA), the second most common autosomal recessive disorder, is caused by the absence of or mutations in the Survival Motor Neuron 1 (SMN1) gene, which encodes an essential protein. A nearly identical copy of the gene, SMN2, fails to compensate for the loss of SMN1 because exon 7 is alternatively spliced, producing a truncated protein, which is unstable. SMN1 and SMN2 differ by a critical C-to-T substitution at position 6 of exon 7 in SMN2 (C6U transition in mRNA). This substitution alone is enough to cause an exon 7 exclusion in SMN2. Various cis- and trans-acting factors have been shown to neutralize the inhibitory effects of C6U transition. Published reports propose models in which either abrogation of an enhancer element associated with SF2/ASF or gain of a silencer element associated with hnRNP A1 is the major cause of exon 7 exclusion in SMN2. Most recent model suggests the presence of an EXtended INhibitory ContexT (Exinct) that is formed as a consequence of C6U transition in exon 7 of SMN2. In Exinct model, several factors may affect exon 7 splicing through cooperative interactions. Such regulation may be common to many alternatively spliced exons in humans. Recent advances in our understanding of SMN gene splicing reveals multiple challenges that are specific to in vivo regulation, which we now know is intimately connected with other biological pathways.

Original languageEnglish (US)
Pages (from-to)271-285
Number of pages15
JournalCritical Reviews in Eukaryotic Gene Expression
Issue number4
StatePublished - Dec 1 2004
Externally publishedYes


  • Alternative splicing
  • Exinct
  • RNA structure
  • SMA
  • SMN
  • cis-elements
  • trans-acting factors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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