Muscleblind proteins regulate alternative splicing

Thai H. Ho, Nicolas Charlet-B, Michael G. Poulos, Gopal Singh, Maurice S. Swanson, Thomas A. Cooper

Research output: Contribution to journalArticlepeer-review

345 Scopus citations


Although the muscleblind (MBNL) protein family has been implicated in myotonic dystrophy (DM), a specific function for these proteins has not been reported. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. Here we demonstrate that MBNL proteins regulate alternative splicing of two pre-mRNAs that are misregulated in DM, cardiac troponin T (cTNT) and insulin receptor (IR). Alternative cTNT and IR exons are also regulated by CELF proteins, which were previously implicated in DM pathogenesis. MBNL proteins promote opposite splicing patterns for cTNT and IR alternative exons, both of which are antagonized by CELF proteins. CELF- and MBNL-binding sites are distinct and regulation by MBNL does not require the CELF-binding site. The results are consistent with a mechanism for DM pathogenesis in which expanded repeats cause a loss of MBNL and/or gain of CELF activities, leading to misregulation of alternative splicing of specific pre-mRNA targets.

Original languageEnglish (US)
Pages (from-to)3103-3112
Number of pages10
JournalEMBO Journal
Issue number15
StatePublished - Aug 4 2004


  • Alternative splicing
  • CELF proteins
  • CUG-BP1
  • Muscleblind
  • Myotonic dystrophy

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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