International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

Table of Contents * Complex Genetics * Developmental Genetics * Gene Annotation * Gene Discovery * Genome Sequencing * Functional Genomics * Mutagenesis * Presentations * Verne Chapman Memorial Lecture

Dr. John Porter
Case Western Reserve University
Department of Ophthalmology
Case Western Reserve University
Cleveland
OH 44106-5068
USA

Co-Authors: Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J, Andrade, FH
Institutions: Department of Opthalmology, The Research Institute of University Hospitals of Cleveland and Case Western Reserve University

Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but lack of dystrophin does not invariably produce necrosis in all muscles/life stages/ species. A compelling example is the total sparing of extraocular muscle (EOM) in all known DMD models. Using DNA microarray in mdx vs. control mice, we screened ~10K genes to establish a molecular signature of dystrophinopathy in affected (hindlimb) and spared (EOM) muscles. In hindlimb, data show that secondary mechanisms are essential contributors to pathogenesis. Using robust and conservative data analyses, we identified 249 differentially expressed genes (212 known/37 ESTs) in mdx hindlimb, > 75% of which were not previously reported in human or animal dystrophies. Many relate to a dominant inflammatory response and extracellular matrix and muscle regeneration gene up-regulation, representing potential therapeutic targets not previously recognized. By contrast, when compared to controls, mdx EOM exhibited nearly no expression changes (down-regulated: Dmd, erythroid differentiation regulator, & an EST;  up-regulated: Alrp & Mt2). The differentially expressed genes in EOM did not constitute a pattern of pathologic or adaptive responses. These data suggest that constitutive properties are responsible for EOM sparing in dystrophinopathy. Candidate genes for EOM sparing were identified on the basis of statistical probabilities and may open new treatment avenues for DMD.