TRANSCRIPTOME 2002: From Functional Genomics to Systems Biology
March 10-13, 2002
Seattle, Washington, USA


Defining Disease Pathogenesis by Comparative Cross-Species Profiling in Human and Mouse Knock-Outs: the Downstream Consequences of Dystrophin Deficiency

Eric P. Hoffman1, Livia Pasquali1, Po Zhao1, Ksenija Gorni1, Frank W. Booth2, Brian Tseng2, Yi-Wen Chen1, 1Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 2Department of Veterinary Biomedical Sciences, University of Missouri at Columbia, Columbia, MO

The absence of dystrophin protein leads to different phenotypes in different species, despite complete loss of dystrophin in all muscles. Human DMD patients show chronic degeneration/regeneration with progressive muscle wasting and an early death.  The mdx mouse initially shows normal muscle, with widespread skeletal muscle necrosis at the age of 3-4 weeks, followed by “successful” muscle fiber regeneration.  We hypothesized that comparison of 60,000-gene profiles in human DMD muscle (U95 GeneChip series and custom Affymetrix MuscleChip), and 36,000-gene profiles in mdx and experimental muscle regeneration (U74 GeneChip series) would identify differentially expressed genes as potential candidates for conferring protection to murine dystrophin deficient muscle.  These same genes would be targets for modulation of the progressive pathology of the human disease.  We used as a starting point a “late muscle regeneration cluster” gleaned from a 27 time-point murine regeneration series.  We then compared the expression of these genes in dystrophin-deficient mdx mouse muscle and human DMD muscle.  We then generated genelists of those genes upregulated in both mouse models, but not upregulated in DMD. Our true genome-wide cross-species comparative candidate gene analysis showed inhibitors of negative regulators of skeletal muscle mass, specific cell division and differentiation genes, and specific connective tissue modulatory genes as candidates for the species-specific response to dystrophin-deficiency.