The molecular genetic basis of myophosphorylase deficiency (McArdle's disease).

Glycogen phosphorylase catalyzes the first step of glycogen catabolism. Hereditary defects of muscle phosphorylase lead to a myopathy characterized by exercise intolerance, cramps, and myoglobinuria (McArdle's disease). We have identified ten mutations in the myophosphorylase gene in patients with McArdle's disease. Relatively common mutations include: a nonsense mutation, CGA(Arg) to TGA at codon 49, observed in 30 of 40 American patients; deletion of a single codon 708/709, observed in 4 of 7 Japanese patients; and a missense mutation, GGC(Gly) to AGC(Ser) at codon 204, observed in 5 of 40 American patients. Apparently rare mutations include: a splice-junction mutation, G to A, at the first nt of intron 14; a deletion of G at codon 510; a mutation, ATG to CTG, in the translation initiation codon; and missense mutations, AAG(Lys) to ACG(Thr) at codon 542, CTG(Leu) to CCG(Pro) at codon 396, CTG(Leu) to CCG(Pro) at codon 291, and GAG(Glu) to AAG(Lys) at codon 654. As most mutations can be screened for using genomic DNA, patients can now be diagnosed reliably using peripheral blood cells, thus avoiding muscle biopsy. Although these findings define the wide spectrum of genetic lesions causing McArdle's disease, the clinical heterogeneity of this disorder remains to be explained.