Large Animal Core

Identification of dystrophin as the defective protein in Duchenne muscular dystrophy (DMD) has allowed critical assessment of potential animal models. Spontaneous forms of X-linked muscular dystrophy due to dystrophin deficiency have been identified in mice, multiple dog breeds, and cats. Over the past 20 years, w e have conducted extensive studies in golden retrievers with muscular dystrophy (GRMD). Our colony of affected dogs was initially established at North Carolina State University in the late '80's and was moved to the University of Missouri in 1994. Additional studies have been completed in German shorthair pointers, Welsh corgis, and Yorkshire terriers.

An RNA processing error in GRMD results from a single base change in the 3' consensus splice site of intron 6 (Sharp et al, 1991). Exon 7 is consequently skipped during RNA processing. The resulting transcript predicts that the dystrophin reading frame is terminated within its N-terminal domain in exon 8. A truncated, apparently unstable dystrophin molecule is produced. German Shorthaired pointers have a large DNA deletion, essentially amounting to a dystrophin "knock out (Schatzberg et al, 1999). We have both golden retrievers and German Shorthaired pointers available for studies. The genomic lesion has not been defined in Welsh Corgis or Yorkshire terriers.

So as to better utilize the GRMD model in therapeutic trials, we have developed various phenotypic tests to objectively characterize disease progression. Affected dogs have marked joint contractures (Kornegay et al, 1994a) and demonstrate weakness of individual (Kornegay et al, 1994b) and grouped muscles (Kornegay et al, 1999). Results from these tests tend to correlate with one another and with other clinicopathologic features. Importantly, by comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease.