An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy

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

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

SMN1 and SMN2 represent the two nearly identical copies of the survival of motor neuron gene in humans. The most frequent cause of spinal muscular atrophy (SMA) is loss of SMN1 accompanied by the inability of SMN2 to compensate due to an inhibitory mutation at position 6 in exon 7 (C6U) that causes exon 7 exclusion. How this single exonic nucleotide regulates exon 7 recognition has been of major interest. Based on score matrices and in vitro assays, abrogation of an exonic splicing enhancer (ESE) associated with SF2/ASF has been considered as the cause of exon 7 exclusion. However, a recent report supports the creation of an exonic splicing silencer (ESS) associated with hnRNP A1 as the determining factor for exon 7 exclusion. Here we show that C6U strengthens an inhibitory context that covers a larger sequence than the hnRNP A1 binding site. The inhibitory context can also be strengthened by the addition of a G residue at the first position of exon 7 in SMN1, promoting exon 7 skipping despite the presence of SF2/ASF binding site. Through in vivo selection and a series of mutations we demonstrate that the strengthening of the extended inhibitory context at the 5′ end of exon 7 is exercised through overlapping sequence motifs that collaborate to regulate exon usage.

Original languageEnglish (US)
Pages (from-to)381-388
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume315
Issue number2
DOIs
StatePublished - Mar 5 2004
Externally publishedYes

Fingerprint

Spinal Muscular Atrophy
Exons
Binding Sites
Mutation
Motor Neurons
Neurons
Assays
Nucleotides
Genes

Keywords

  • Alternative pre-mRNA splicing
  • Exon 7
  • Exonic splicing enhancer
  • SMN genes
  • Spinal muscular atrophy

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. / Singh, Natalia N.; Androphy, Elliot; Singh, Ravindra N.

In: Biochemical and Biophysical Research Communications, Vol. 315, No. 2, 05.03.2004, p. 381-388.

Research output: Contribution to journalArticle

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