Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy

Nat Genet. 2001 Sep;29(1):40-7. doi: 10.1038/ng704.


Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide expansion in the 3' untranslated region of the DM protein kinase gene. People with DM1 have an unusual form of insulin resistance caused by a defect in skeletal muscle. Here we demonstrate that alternative splicing of the insulin receptor (IR) pre-mRNA is aberrantly regulated in DM1 skeletal muscle tissue, resulting in predominant expression of the lower-signaling nonmuscle isoform (IR-A). IR-A also predominates in DM1 skeletal muscle cultures, which exhibit a decreased metabolic response to insulin relative to cultures from normal controls. Steady-state levels of CUG-BP, a regulator of pre-mRNA splicing proposed to mediate some aspects of DM1 pathogenesis, are increased in DM1 skeletal muscle; overexpression of CUG-BP in normal cells induces a switch to IR-A. The CUG-BP protein mediates this switch through an intronic element located upstream of the alternatively spliced exon 11, and specifically binds within this element in vitro. These results support a model in which increased expression of a splicing regulator contributes to insulin resistance in DM1 by affecting IR alternative splicing.

Publication types

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

MeSH terms

  • Alternative Splicing*
  • Base Sequence
  • Cells, Cultured
  • DNA Primers
  • Humans
  • Insulin Resistance / genetics*
  • Muscle, Skeletal / metabolism
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / physiopathology
  • Protein Isoforms / genetics
  • RNA / genetics
  • Receptor, Insulin / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trinucleotide Repeats


  • DNA Primers
  • Protein Isoforms
  • RNA
  • Receptor, Insulin