Molecular diagnosis of McArdle disease: revised genomic structure of the myophosphorylase gene and identification of a novel mutation.

McArdle disease is a rare autosomal recessive disorder of the muscle glycogen metabolism caused by mutations in the muscle glycogen phosphorylase gene. Until now, a total number of 11 different mutations in the coding region or splice sites of the myophosphorylase gene have been identified. In contrast to a wealth of data on the RNA and protein level, little information is available on the genomic sequence of the corresponding gene. To facilitate molecular diagnosis of McArdle disease, we reinvestigated the genomic structure of the myophosphorylase gene and sequenced about 9.8 kilobases (kb) on the genomic level. By choosing 14 intronic primer pairs, we were able to amplify the complete human coding sequence as well as the adjacent splice sites of the 20 exons. Direct sequencing of the amplification products of a consanguineous Turkish family with typical McArdle disease revealed a novel single base pair deletion in exon 18, which predicts a frameshift and a premature termination of the protein. In summary, we established a system for molecular diagnosis of McArdle disease based on a revised genomic structure of the myophosphorylase gene and demonstrated its feasibility by identification of a novel mutation.