Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1

Nat Genet. 2002 Apr;30(4):377-84. doi: 10.1038/ng854. Epub 2002 Mar 4.


Alteration of correct splicing patterns by disruption of an exonic splicing enhancer may be a frequent mechanism by which point mutations cause genetic diseases. Spinal muscular atrophy results from the lack of functional survival of motor neuron 1 gene (SMN1), even though all affected individuals carry a nearly identical, normal SMN2 gene. SMN2 is only partially active because a translationally silent, single-nucleotide difference in exon 7 causes exon skipping. Using ESE motif-prediction tools, mutational analysis and in vivo and in vitro splicing assays, we show that this single-nucleotide change occurs within a heptamer motif of an exonic splicing enhancer, which in SMN1 is recognized directly by SF2/ASF. The abrogation of the SF2/ASF-dependent ESE is the basis for inefficient inclusion of exon 7 in SMN2, resulting in the spinal muscular atrophy phenotype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Base Sequence
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein
  • DNA Mutational Analysis
  • Exons*
  • Humans
  • Introns
  • Models, Genetic
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal / genetics*
  • Mutagenesis, Site-Directed
  • Mutation
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Phenotype
  • Point Mutation
  • Protein Biosynthesis
  • RNA / metabolism
  • RNA Splicing*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • SMN Complex Proteins
  • Sequence Homology, Nucleic Acid
  • Serine-Arginine Splicing Factors
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Transcription, Genetic
  • Transfection
  • Ultraviolet Rays


  • Cyclic AMP Response Element-Binding Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • SMN Complex Proteins
  • SMN1 protein, human
  • SMN2 protein, human
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Serine-Arginine Splicing Factors
  • RNA