Human Molecular Genetics Advance Access originally published online on January 20, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 6 589-600
DOI: 10.1093/hmg/ddh064
Inhibition of myogenesis in transgenic mice expressing the human DMPK 3'-UTR
1Solange Gauthier–Karsh Molecular Genetics Laboratory, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Rd, Ottawa, Ontario, Canada K1H 8L1, 2Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5, 3Ottawa Hospital Research Institute Neuroscience Program, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5, 4Department of Biochemistry and Molecular Biology, University of Calgary, 2500 University Drive NW, Calgary, AB, Canada, T2N 1N4, 5Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5 and 6NeuroGenes Project, International Cooperative Research Project/Japan Science and Technology Corporation, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Rd, Ottawa, Ontario, Canada K1H 8L1
Received September 24, 2003; Revised January 4, 2004; Accepted January 12, 2004
Myotonic dystrophy (DM1) is a multisystemic disorder caused by a CTG repeat expansion within the 3'-UTR of the DMPK gene. DM1 is characterized by delayed muscle development, muscle weakness and wasting, cardiac conduction abnormalities, cognitive defects and cataracts. Recent studies have demonstrated that the disease mechanism involves a dominant gain-of-function conferred upon mutant transcripts by expanded repeats. However, further attempts to model aspects of DM muscle pathology in cultured myoblasts suggest that 3'-UTR sequences flanking the CTG repeat tract are also required for full expression of the disease phenotype. Here, we report that overexpression of the DMPK 3'-UTR including either wild-type (11) or expanded (91) CTG repeats results in aberrant and delayed muscle development in fetal transgenic mice. In addition, transgenic animals with both expanded and wild-type CTG repeats display muscle atrophy at 3 months of age. Primary myoblast cultures from both 11 and 91 repeat mice display reduced fusion potential, but a greater reduction is observed in the 91 repeat cultures. Taken together, these data indicate that overexpression of the DMPK 3'-UTR interferes with normal muscle development in mice and that this is exacerbated by inclusion of a mutant repeat. This suggests that the delayed muscle development in DM1 involves an interplay between the expanded CTG repeat and adjacent 3'-UTR sequences.
* To whom correspondence should be addressed. Tel: +1 6137383281; Fax: +1 6137384833; E-mail: bob{at}mgcheo.med.uottawa.ca
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