AUTOSOMAL GLYCOGENOSIS OF LIVER AND MUSCLE DUE TO PHOSPHORYLASE-KINASE DEFICIENCY IS CAUSED BY MUTATIONS IN THE PHOSPHORYLASE-KINASE BETA-SUBUNIT (PHKB)

Glycogen storage disease due to phosphorylase kinase deficiency occurs in several variants that differ in mode of inheritance and tissue-spe cificity. This heterogeneity is suspected to be largely due to mutatio ns affecting different subunits and isoforms of phosphorylase kinase, The gene of the ubiquitously expressed beta subunit, PHKB, was a candi date for involvement in autosomally transmitted phosphorylase kinase d eficiency of liver and muscle, To identify such mutations, the complet e PHKB coding sequence was amplified by RT-PCR of RNA isolated from bl ood samples of patients and analyzed by direct sequencing of PCR produ cts, The characterization of mutations was complemented by PCR of geno mic DNA, In one female and four male patients, we identified five inde pendent nonsense mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter i n two cases), one single-base insertion in codon N421, one splice-site mutation affecting exon 31, and a large deletion involving the loss o f exon 8, Although these severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, they are associated with a surpris ingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of similar to 10%.