Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing

Mol Cell. 2002 Jul;10(1):45-53. doi: 10.1016/s1097-2765(02)00572-5.


Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder caused by a CTG expansion in the 3' untranslated region of the DMPK gene. A predominant characteristic of DM1 is myotonia resulting from skeletal muscle membrane hyperexcitability. Here we demonstrate loss of the muscle-specific chloride channel (ClC-1) mRNA and protein in DM1 skeletal muscle tissue due to aberrant splicing of the ClC-1 pre-mRNA. The splicing regulator, CUG binding protein (CUG-BP), which is elevated in DM1 striated muscle, binds to the ClC-1 pre-mRNA, and overexpression of CUG-BP in normal cells reproduces the aberrant pattern of ClC-1 splicing observed in DM1 skeletal muscle. We propose that disruption of alternative splicing regulation causes a predominant pathological feature of DM1.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics*
  • Base Sequence
  • Blotting, Western
  • Chloride Channels / genetics*
  • Chloride Channels / metabolism*
  • Humans
  • Introns
  • Molecular Sequence Data
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Myotonic Dystrophy / classification
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / metabolism*
  • Myotonic Dystrophy / pathology
  • Organ Specificity
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • CLC-1 channel
  • Chloride Channels
  • RNA Precursors
  • RNA, Messenger