Somatic reversion/suppression of the mouse mdx phenotype in vivo

Abstract

The mdx mouse has a myopathy caused by dystrophin deficiency, and is therefore biochemically and genetically homologous to human Duchenne muscular dystrophy. While mdx mouse muscle shows no dystrophin by immunoblotting, a very small percentage of myofibers appear clearly dystrophin-positive by immunofluorescence microscopy. We have characterized these rare positive-staining fibers, and conclude that they are indeed expressing dystrophin despite a nonsense mutation within the dystrophin gene. Thus, the dystrophin-positive fibers probably represent somatic reversion or suppression of the mdx mutation. Cardiac muscle and skeletal muscle from mdx mice showed dramatically different patterns of dystrophin-positive cells. However, this difference is expected given the apparent clonal nature of the reversion/suppression events, the inability of cardiac muscle to regenerate, and other differences in the developmental programs of myofibers and cardiocytes. The prevalence of dystrophin-positive cells in mdx cardiac muscle was determined to be approximately 2 x 10(-5). The observed prevalence of dystrophin-positive cardiocytes in the mdx mouse is a possible estimate of the somatic reversion rate of the mdx mutation in vivo.