Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2

PLoS One. 2013 Dec 20;8(12):e83777. doi: 10.1371/journal.pone.0083777. eCollection 2013.

Abstract

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alternative Splicing
  • CELF1 Protein
  • Case-Control Studies
  • Chloride Channels / genetics
  • Gene Expression Regulation*
  • Humans
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Myotonic Dystrophy / genetics*
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Young Adult

Substances

  • CELF1 Protein
  • CELF1 protein, human
  • CLC-1 channel
  • CNBP protein, human
  • Chloride Channels
  • MBNL1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A1 protein, human

Grant support

This research was funded by FMM-Fondazione Malattie Miotoniche, AFM-Association Francaise contre les Myopathies and Agenzia Spaziale Italiana (ASI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.