Human Molecular Genetics Advance Access originally published online on April 20, 2005
Human Molecular Genetics 2005 14(11):1539-1547; doi:10.1093/hmg/ddi162
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Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy
1Department of Pathology, 2Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA, 3Department of Pediatrics and 4Department of Pathology, Texas Children's Hospital, 6621 Fannin, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 7137983141; Fax: +1 7137985838; Email: tcooper{at}bcm.tmc.edu
Received February 23, 2005; Accepted April 12, 2005
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.
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