Small molecule kinase inhibitors alleviate different molecular features of myotonic dystrophy type 1

RNA Biol. 2014;11(6):742-54. doi: 10.4161/rna.28799. Epub 2014 Apr 24.


Expandable (CTG)n repeats in the 3' UTR of the DMPK gene are a cause of myotonic dystrophy type 1 (DM1), which leads to a toxic RNA gain-of-function disease. Mutant RNAs with expanded CUG repeats are retained in the nucleus and aggregate in discrete inclusions. These foci sequester splicing factors of the MBNL family and trigger upregulation of the CUGBP family of proteins resulting in the mis-splicing of their target transcripts. To date, many efforts to develop novel therapeutic strategies have been focused on disrupting the toxic nuclear foci and correcting aberrant alternative splicing via targeting mutant CUG repeats RNA; however, no effective treatment for DM1 is currently available. Herein, we present results of culturing of human DM1 myoblasts and fibroblasts with two small-molecule ATP-binding site-specific kinase inhibitors, C16 and C51, which resulted in the alleviation of the dominant-negative effects of CUG repeat expansion. Reversal of the DM1 molecular phenotype includes a reduction of the size and number of foci containing expanded CUG repeat transcripts, decreased steady-state levels of CUGBP1 protein, and consequent improvement of the aberrant alternative splicing of several pre-mRNAs misregulated in DM1.

Keywords: CUG Foci; CUGBP1 protein; MBNL1 protein; RNA splicing; RNA-binding proteins; myotonic dystrophy; protein kinases; protein phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • CELF1 Protein
  • Cells, Cultured
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Myotonic Dystrophy / drug therapy
  • Myotonic Dystrophy / enzymology
  • Myotonic Dystrophy / genetics*
  • Phosphotransferases / antagonists & inhibitors*
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • RNA Precursors
  • RNA Splicing
  • RNA, Messenger
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Transcription, Genetic


  • CELF1 Protein
  • CELF1 protein, human
  • Enzyme Inhibitors
  • MBNL1 protein, human
  • RNA Precursors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Phosphotransferases