Human Molecular Genetics, 2001, Vol. 10, No. 24 2745-2750
© 2001 Oxford University Press
Suppression of revertant fibers in mdx mice by expression of a functional dystrophin
1Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109-0618, USA, 2Muscle Cell Biology, Medical Research Council Clinical Science Center, Hammersmith Hospital, London W12 ONN, UK, 3Department of Neurology, University of Washington, Seattle, WA, 98195-7720, USA
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration that results from the absence of dystrophin. Despite null mutations in the dystrophin gene, many DMD patients display a low percentage of dystrophin-positive fibers. These ‘revertant fibers’ are also present in the dystrophin-deficient mdx mouse and are believed to result from alternative splicing or second mutation events that bypass the mutation and restore an open reading frame. However, it is unclear what role dystrophin and the dystrophic pathology might play in revertant fiber formation and accumulation. We have analyzed the role of dystrophin expression and the dystrophic pathology in this process by monitoring revertant fibers in transgenic mdx mice that express truncated dystrophins. We found that newborn transgenic mice displayed approximately the same number of revertant fibers as newborn mdx mice, indicating that expression of a functional dystrophin does not suppress the initiation of revertant fiber formation. Surprisingly, when the transgene encoded a functional dystrophin, revertant fibers were not detected in adult or old mdx mice. In contrast, adult transgenic mice expressing a non-functional dystrophin accumulated increasing numbers of revertant fibers, similar to mdx mice, suggesting that positive selection is required for the persistence of revertant fibers. Finally, we provide evidence that the loss of revertant dystrophin in transgenic mdx muscle fibers overexpressing a functional dystrophin results from displacement of the revertant protein by the transgene-encoded dystrophin.
+ To whom correspondence should be addressed at: Department of Neurology, University of Washington School of Medicine, K243 HSB, Box 357720, Seattle, WA 98195-7720, USA. Tel: +1 206 221 5363; Fax: +1 206 616 8272; Email: jsc5@u.washington.edu
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