title: Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy.
abstract: Myotonic dystrophy type I (DM1) is an RNA-mediated disease caused by a non-coding CTG repeat expansion. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. A link has been established between splicing regulation by CUG-BP1, a member of the CELF family of proteins, and DM1 pathogenesis. To determine whether increased CUG-BP1 function was sufficient to model DM, transgenic mice overexpressing CUG-BP1 (MCKCUG-BP1) in heart and skeletal muscle, two tissues affected in DM1, were generated. Histological and electron microscopic analyses of skeletal muscle reveal common pathological features with DM tissues: chains of central nuclei, degenerating fibers and centralized NADH reactivity. MCKCUG-BP1 mice have disrupted splicing of three CELF target pre-mRNAs, cardiac troponin T (Tnnt2), myotubularin-related 1 gene (Mtmr1) and the muscle-specific chloride channel (Clcn1), consistent with that observed in DM heart and skeletal muscle. The results are consistent with a mechanism for DM pathogenesis in which expanded repeats result in increased CUG-BP1 activity and/or other CELF family members and have trans-dominant effects on specific pre-mRNA targets.
authors.affiliation: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.forename: Donnie
authors.initials: D
authors.lastname: Bundman
authors.forename: Dawna L
authors.initials: DL
authors.lastname: Armstrong
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D000067879:CELF1 Protein; D017931:DNA Primers; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D017931:DNA Primers; D016601:RNA-Binding Proteins