Gain of RNA function in pathological cases: Focus on myotonic dystrophy

Biochimie. 2011 Nov;93(11):2006-12. doi: 10.1016/j.biochi.2011.06.028. Epub 2011 Jul 13.


Expansion of repeated sequences in non-coding regions of different genes causes a number of inherited diseases including myotonic dystrophies, Huntington disease-like 2, Fragile X tremor/ataxia syndrome and spinocerebellar ataxia 8, 10, 12, 31. Involvement of an RNA gain-of-function mechanism in pathological case has been described and studied in-depth in myotonic dystrophy type 1 (DM1). This inherited neuromuscular disorder is caused by a (CTG)n >50 expansion in the 3' non-coding region of the dystrophia myotonica-protein kinase (DMPK) gene. Expanded CUG transcripts (CUGexp-RNAs) are sequestered in the nucleus within small aggregates and interfere with the regulatory splicing activities of MBNL1 and CELF1 RNA-binding proteins, leading to the misregulation of the alternative splicing of several transcripts. Despite the relevance of aberrant splicing events in this complex pathology, the CUGexp-RNAs trans-dominant effects alter other splicing-independent processes that may also contribute to DM1 pathogenesis. This review will focus on toxic RNA gain-of-function as a pathologic mechanism for DM1 and other repeat expansion disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alternative Splicing / genetics
  • CELF1 Protein
  • Humans
  • Mutation
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / pathology
  • Myotonin-Protein Kinase
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA / genetics*
  • RNA / metabolism*
  • RNA Splicing / genetics
  • RNA, Untranslated / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Trinucleotide Repeat Expansion / genetics*


  • CELF1 Protein
  • CELF1 protein, human
  • DMPK protein, human
  • MBNL1 protein, human
  • RNA, Untranslated
  • RNA-Binding Proteins
  • RNA
  • Myotonin-Protein Kinase
  • Protein-Serine-Threonine Kinases