Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy.
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.
Savkur
R S
RS
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
Philips
A V
AV
Cooper
T A
TA
D017398:Alternative Splicing; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics; D012313:RNA / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018911:Trinucleotide Repeats
D017931:DNA Primers; D020033:Protein Isoforms; D012313:RNA; D011972:Receptor, Insulin