Human Molecular Genetics Advance Access published online on April 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi162
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1 Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
* To whom correspondence should be addressed. 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 if 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 EM analysis of skeletal muscle reveals 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.
Received February 23, 2005
Revised April 12, 2005
Accepted April 12, 2005
Article
Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy
2 Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
3 Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, 6621 Fannin, Houston, TX 77030, USA; Department of Pathology, Texas Children's Hospital, 6621 Fannin, Houston, TX 77030, USA
Thomas A. Cooper, E-mail: tcooper{at}bcm.tmc.edu
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