An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: Potential therapy of SMA

M. L. Zhang, C. L. Lorson, E. J. Androphy, J. Zhou

Research output: Contribution to journalArticle

100 Scopus citations


Spinal muscular atrophy (SMA) is a degenerative motor neuron disorder resulting from homozygous loss of the SMN1 gene. SMN2, a nearly identical copy gene, is preserved in SMA patients. A single nucleotide difference between SMN1 and SMN2 causes exon 7 skipping in the majority of SMN2 mRNA. Gene therapy through modulation of SMN2 gene transcription in SMA patients may be possible. We constructed a series of SMN mini-genes comprised of SMN exon 6 to exon 8 sequences fused to green fluorescence protein (GFP) or luciferase reporters, to monitor SMN exon 7 splicing. These reporters recapitulated the splicing patterns of the endogenous SMN gene in stable cell lines. The SMN1-luciferase reporter was approximately 3.5-fold more active than SMN2-luciferase and SMN1-GFP intensities were visually distinguishable from SMN2-GFP. We have screened chemical inducers and inhibitors of kinase pathways using stable SMN-reporter lines and found that the phosphatase inhibitor sodium vanadate specifically stimulated exon 7 inclusion within SMN2 mRNAs. This is the first compound identified that can stimulate exon 7 inclusion into transcripts derived from the endogenous SMN2 gene. These results demonstrate that this system can be utilized to identify small molecules that regulate the splicing of SMN exon 7.

Original languageEnglish (US)
Pages (from-to)1532-1538
Number of pages7
JournalGene Therapy
Issue number20
StatePublished - Nov 26 2001
Externally publishedYes


  • Gene therapy
  • High throughput screening (HTS)
  • Small molecules
  • Spinal muscular atrophy (SMA)
  • Splicing
  • Survival motor neuron (SMN)

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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