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Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2

Anna Vihola1, Linda L Bachinski, Mario Sirito

  • 1Department of Medical Genetics, Folkhälsan Institute of Genetics, University of Helsinki, 00014 Helsinki, Finland.

Acta Neuropathologica
|January 13, 2010
PubMed

Insights

Myotonic dystrophies type 1 and 2 (DM1 and DM2) show distinct molecular differences in gene splicing and myosin expression, impacting muscle function. These findings offer new insights into the varying muscle involvement in DM1 and DM2.

Area of Science:

  • Molecular Biology
  • Genetics
  • Neuromuscular Disorders

Background:

  • Myotonic dystrophies type 1 (DM1) and type 2 (DM2) share complex phenotypes, but the precise molecular basis for muscle weakness and differential muscle involvement remains unclear.
  • RNA-mediated toxic gain-of-function is implicated in DM1 and DM2 pathogenesis, affecting gene transcription and mRNA processing.

Purpose of the Study:

  • To investigate the molecular differences in gene expression and splicing between DM1 and DM2.
  • To elucidate the molecular basis of muscle weakness and differential muscle involvement in DM1 and DM2.

Main Methods:

  • Microarray profiling of mRNA expression for muscle-specific genes and transcription factors.
  • Analysis of abnormal splicing in selected genes.
  • Protein level analysis of abnormally regulated genes.

Main Results:

  • Differential abnormal splicing of TNNT3 and LDB3 genes observed, with more pronounced patterns in DM2 compared to DM1.
  • Global abnormalities in myosin isoforms, including increased transcript levels in both DM1 and DM2.
  • Distinct myosin isoform expression in atrophic muscle fibers: DM2 exclusively fast myosin, DM1 co-expression of fast and slow myosin.

Conclusions:

  • Abnormal splicing of TNNT3 and LDB3 represents a key molecular distinction between DM1 and DM2.
  • Differential myosin isoform expression in atrophic fibers contributes to the distinct muscle pathology in DM1 and DM2.
  • Aberrant protein translation and/or turnover may also play a role in the pathogenesis of myotonic dystrophies.

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