Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy

Nat Struct Mol Biol. 2010 Feb;17(2):187-93. doi: 10.1038/nsmb.1720. Epub 2010 Jan 24.


The common form of myotonic dystrophy (DM1) is associated with the expression of expanded CTG DNA repeats as RNA (CUG(exp) RNA). To test whether CUG(exp) RNA creates a global splicing defect, we compared the skeletal muscle of two mouse models of DM1, one expressing a CTG(exp) transgene and another homozygous for a defective muscleblind 1 (Mbnl1) gene. Strong correlation in splicing changes for approximately 100 new Mbnl1-regulated exons indicates that loss of Mbnl1 explains >80% of the splicing pathology due to CUG(exp) RNA. In contrast, only about half of mRNA-level changes can be attributed to loss of Mbnl1, indicating that CUG(exp) RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix proteins. We propose that CUG(exp) RNA causes two separate effects: loss of Mbnl1 function (disrupting splicing) and loss of another function that disrupts extracellular matrix mRNA regulation, possibly mediated by Mbnl2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies.

Publication types

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

MeSH terms

  • Alternative Splicing*
  • Animals
  • DNA-Binding Proteins / deficiency*
  • Disease Models, Animal
  • Extracellular Matrix Proteins / biosynthesis*
  • Gene Expression*
  • Mice
  • Models, Biological
  • Myotonic Dystrophy / genetics*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins
  • Repetitive Sequences, Nucleic Acid*


  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • Mbnl1 protein, mouse
  • RNA, Messenger
  • RNA-Binding Proteins

Associated data

  • GEO/GSE17986