Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin binding in myotonic dystrophy type 1

Neurology. 2008 Feb 26;70(9):677-85. doi: 10.1212/01.wnl.0000302174.08951.cf.


Background: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms in DM1, but the cause of muscle wasting is still unknown. By contrast, many forms of muscular dystrophy are caused by abnormalities of the dystrophin-glycoprotein complex (DGC). alpha-Dystrobrevin is a key component of the DGC in striated muscle and plays important roles in maturation and signal transduction by interacting with alpha-syntrophin. The goal of this study was to investigate alternative splicing of alpha-dystrobrevin in DM1 and examine alpha-syntrophin binding of different alpha-dystrobrevin splice isoforms.

Methods: Splicing patterns of alpha-dystrobrevin in DM1 muscle were studied by reverse-transcriptase PCR. Expression of the variant splice isoform was examined by immunoblotting and immunohistochemistry. Alternatively spliced isoforms were expressed in cultured cells to investigate interaction with alpha-syntrophin. alpha-Syntrophin expression was examined by immunoblotting.

Results: alpha-Dystrobrevin mRNA including exons 11A and 12 was increased in both skeletal and cardiac muscle of DM1 patients. The aberrantly spliced alpha-dystrobrevin isoform was localized to the sarcolemma, and showed increased binding with alpha-syntrophin. Furthermore, levels of alpha-syntrophin associated with the DGC were increased in DM1 muscle.

Conclusion: Alternative splicing of alpha-dystrobrevin is dysregulated in myotonic dystrophy type 1 (DM1) muscle, resulting in changes in alpha-syntrophin binding. These results raise the possibility that effects on alpha-dystrobrevin splicing may influence signaling in DM1 muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alternative Splicing / genetics*
  • Animals
  • Calcium-Binding Proteins / genetics
  • Cell Line
  • Dystrophin-Associated Proteins / genetics*
  • Exons / genetics
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Motor Neuron Disease / genetics
  • Motor Neuron Disease / pathology
  • Muscle Proteins / genetics
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies, Limb-Girdle / genetics
  • Muscular Dystrophies, Limb-Girdle / pathology
  • Myocardium / pathology
  • Myotonic Dystrophy / diagnosis
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / pathology
  • Polymyositis / genetics
  • Polymyositis / pathology
  • RNA Splicing / genetics*
  • Reference Values
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcolemma / pathology
  • Species Specificity
  • Transcription, Genetic / genetics
  • Transfection
  • Trinucleotide Repeats


  • Calcium-Binding Proteins
  • Dystrophin-Associated Proteins
  • Membrane Proteins
  • Muscle Proteins
  • dystrobrevin
  • syntrophin alpha1