Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies

Neuromuscul Disord. 2014 Mar;24(3):227-40. doi: 10.1016/j.nmd.2013.11.001. Epub 2013 Nov 15.

Abstract

The prevailing pathomechanistic paradigm for myotonic dystrophy (DM) is that aberrant expression of embryonic/fetal mRNA/protein isoforms accounts for most aspects of the pleiotropic phenotype. To identify aberrant isoforms in skeletal muscle of DM1 and DM2 patients, we performed exon-array profiling and RT-PCR validation on the largest DM sample set to date, including Duchenne, Becker and tibial muscular dystrophy (NMD) patients as disease controls, and non-disease controls. Strikingly, most expression and splicing changes in DM patients were shared with NMD controls. Comparison between DM and NMD identified almost no significant differences. We conclude that DM1 and DM2 are essentially identical for dysregulation of gene expression, and DM expression changes represent a subset of broader spectrum dystrophic changes. We found no evidence for qualitative splicing differences between DM1 and DM2. While some DM-specific splicing differences exist, most of the DM splicing differences were also seen in NMD controls. SSBP3 exon 6 missplicing was observed in all diseased muscle and led to reduced protein. We conclude there is no widespread DM-specific spliceopathy in skeletal muscle and suggest that missplicing in DM (and NMD) may not be the driving mechanism for the muscle pathology, since the same pathways show expression changes unrelated to splicing.

Keywords: Aberrant isoform expression; DM1; DM2; Missplicing; Myotonic dystrophy.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Exons
  • Female
  • Gene Expression*
  • Humans
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / metabolism
  • Myotonic Disorders / genetics*
  • Myotonic Disorders / metabolism
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Splicing*
  • Young Adult

Substances

  • Protein Isoforms