title: Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1.
abstract: 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.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Misha
authors.initials: M
authors.lastname: Koshelev
authors.forename: Satyam
authors.initials: S
authors.lastname: Sarma
authors.forename: Roger E
authors.initials: RE
authors.lastname: Price
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001835:Body Weight; D000067879:CELF1 Protein; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D020964:Embryo Loss / Q000473:pathology; D006329:Heart Conduction System / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D009223:Myotonic Dystrophy / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D009929:Organ Size; D009928:Organ Specificity; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014463:Ultrasonography
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D016601:RNA-Binding Proteins