Molecular heterogeneity of myophosphorylase deficiency (McArdle's disease): A genotype-phenotype correlation study

We report on 54 Spanish patients with McArdle's disease from 40 unrelated f amilies. Molecular analysis revealed that the most common R49X mutation was present in 70% of patients and 55% of alleles. The G204S mutation was less frequent and found in 14.8% of patients and 9% of mutant alleles. The W797 R mutation was observed in 16.5% of patients, accounting for 13.7% of mutan t alleles. Moreover, 78% of mutant alleles among Spanish patients can be id entified by using polymerase chain reaction-restriction fragment length pol ymorphism analysis for the R49X, G204S, and W797R mutations, which makes no ninvasive diagnosis possible through molecular genetic analysis of blood DN A. Six novel mutations were found. Three were missense mutations, E348K, R6 01W, and A703V; two nonsense mutations, E124X and Q754X; and one single bas e pair deletion, 533 delA. No dear genotype-phenotype correlation emerges f rom our study. Most of the mutations of uncharged and solvent inaccessible residues and the truncations must disrupt the basic structure of the protei n. The mutations of charged residues would be expected to interfere with in ternal hydrogen bonding networks, introducing severe incompatible partnerin g that is caused by poor packing or electrostatic repulsions.