Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2

PLoS One. 2014 Apr 10;9(4):e93983. doi: 10.1371/journal.pone.0093983. eCollection 2014.


Myotonic dystrophy type 2 (DM2) is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG) repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR), we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Alternative Splicing*
  • Biopsy
  • Calcium Signaling
  • Cell Survival
  • Computational Biology
  • Exons
  • Female
  • Fetal Proteins / genetics
  • Formins
  • Gene Expression Regulation
  • Genome, Human*
  • Humans
  • LIM Domain Proteins / genetics
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • Myotonic Dystrophy / genetics*
  • NFI Transcription Factors / genetics
  • Nuclear Proteins / genetics
  • Polymerase Chain Reaction
  • RNA / metabolism
  • RNA-Binding Proteins / genetics
  • tau Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • FHOD1 protein, human
  • Fetal Proteins
  • Formins
  • LDB3 protein, human
  • LIM Domain Proteins
  • MAPT protein, human
  • MBNL1 protein, human
  • NFI Transcription Factors
  • NFIX protein, human
  • Nuclear Proteins
  • RNA-Binding Proteins
  • tau Proteins
  • RNA

Grant support

This work was supported by Ministero della Salute and Associazione Italiana per la Ricerca sul Cancro (Grant AIRC IG-11436). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.