Genetic defects of myophosphorylase in humans cause a metabolic myopathy (McArdle's disease) characterized by exercise intolerance, cramps, and recurrent myoglobinuria. Recently, a breed of cattle with myophosphorylase deficiency has been identified: this is the first animal model of McArdle's disease. To define the molecular genetic error in the cattle, we cloned and sequenced the wild-type bovine myophosphorylase cDNA. Homology to human cDNA is 95.8% for the amino acid sequence, and 92.0% for the nucleotide sequence. Sequence homology to rabbit cDNA is 97.3% in amino acid, 90.8% in nucleotide. In the cDNA fragments amplified by RT-PCR from muscle RNA of the cattle with myophosphorylase deficiency, we identified a C-to-T substitution, changing an encoded arginine (CGG) to tryptophan (TGG) at codon 489. The mutant residue is adjacent to pyridoxal phosphate binding sites and to an active site residue, and the sequence around this mutation is highly conserved in different species.
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Acknowledgements--This work was supported by National Institutes of Health grant NS 11766 and by a grant from the Muscular Dystrophy Association.
- Animal model
- Gene defect
- Myophosphorylase deficiency