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Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion within the 3'-untranslated region of the DMPK gene. The predominant mechanism of pathogenesis is a toxic gain of function of CUG repeat containing RNA transcribed from the expanded allele. The molecular mechanisms by which the RNA containing expanded repeats produce pathogenic effects include: sequestration of muscleblind-like 1 (MBNL1) protein and up-regulation of CUG binding protein 1 (CUGBP1). MBNL1 and CUGBP1 are RNA binding proteins that regulate alternative splicing transitions during development. Altered functions of these proteins in DM1 lead to misregulated splicing of their target genes, resulting in several features of the disease. The role of MBNL1 depletion in DM1 is well established through a mouse knock-out model that reproduces many disease features. Here we directly test the hypothesis that CUGBP1 up-regulation also contributes to manifestations of DM1. Using tetracycline-inducible CUGBP1 and heart-specific reverse tetracycline trans-activator transgenes, we expressed human CUGBP1 in adult mouse heart. Our results demonstrate that up-regulation of CUGBP1 is sufficient to reproduce molecular, histopathological and functional changes observed in a previously described DM1 mouse model that expresses expanded CUG RNA repeats as well as in individuals with DM1. These results strongly support a role for CUGBP1 up-regulation in DM1 pathogenesis.

Pubmed ID: 20051426


  • Koshelev M
  • Sarma S
  • Price RE
  • Wehrens XH
  • Cooper TA


Human molecular genetics

Publication Data

March 15, 2010

Associated Grants

  • Agency: NINDS NIH HHS, Id: F30 NS061358
  • Agency: NINDS NIH HHS, Id: F30NS61358-01
  • Agency: NIAMS NIH HHS, Id: R01 AR045653
  • Agency: NHLBI NIH HHS, Id: R01 HL045565
  • Agency: NHLBI NIH HHS, Id: R01 HL091947
  • Agency: NHLBI NIH HHS, Id: R01 HL091947-01A2
  • Agency: NHLBI NIH HHS, Id: R01 HL117641
  • Agency: PHS HHS, Id: R01089598
  • Agency: PHS HHS, Id: R01091947
  • Agency: NIAMS NIH HHS, Id: R01AR45653
  • Agency: NIGMS NIH HHS, Id: R01GM076493

Mesh Terms

  • Alternative Splicing
  • Animals
  • Body Weight
  • Cardiomyopathy, Dilated
  • Embryo Loss
  • Heart Conduction System
  • Heart Defects, Congenital
  • Humans
  • Mice
  • Mice, Transgenic
  • Myocardium
  • Myotonic Dystrophy
  • Organ Size
  • Organ Specificity
  • RNA-Binding Proteins