Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

J Clin Invest. 2007 Dec;117(12):3952-7. doi: 10.1172/JCI33355.


In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to repetitive action potentials, stiffness, and delayed relaxation. This constellation of features, collectively known as myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (ClC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3' splice site of ClC-1 exon 7a reversed the defect of ClC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in ClC-1 mRNA, upregulated the level of ClC-1 mRNA, increased the expression of ClC-1 protein in the surface membrane, normalized muscle ClC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of ClC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Alternative Splicing / drug effects*
  • Alternative Splicing / genetics
  • Animals
  • Channelopathies / drug therapy*
  • Channelopathies / genetics
  • Channelopathies / metabolism
  • Chloride Channels / biosynthesis*
  • Chloride Channels / genetics
  • Exons / genetics
  • Mice
  • Myotonia Congenita / drug therapy*
  • Myotonia Congenita / genetics
  • Myotonia Congenita / metabolism
  • Myotonic Dystrophy / drug therapy*
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / metabolism
  • Oligodeoxyribonucleotides, Antisense / pharmacology*
  • Oligodeoxyribonucleotides, Antisense / therapeutic use
  • RNA Splice Sites / genetics
  • Sarcolemma / genetics
  • Sarcolemma / metabolism


  • CLC-1 channel
  • Chloride Channels
  • Oligodeoxyribonucleotides, Antisense
  • RNA Splice Sites