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 inseveral variants that differ in mode of inheritance and tissue-specificity. This heterogeneity is suspected to be largely due to mutationsaffecting different subunits and isoforms of phosphorylase kinase. The geneof the ubiquitously expressed beta subunit, PHKB, was a candidate forinvolvement in autosomally transmitted phosphorylase kinase deficiency ofliver and muscle. To identify such mutations, the complete PHKB codingsequence was amplified by RT-PCR of RNA isolated from blood samples ofpatients and analyzed by direct sequencing of PCR products. Thecharacterization of mutations was complemented by PCR of genomic DNA. Inone female and four male patients, we identified five independent nonsensemutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), onesingle-base insertion in codon N421, one splice-site mutation affectingexon 31, and a large deletion involving the loss of exon 8. Although thesesevere translation-disrupting mutations occur in constitutively expressedsequences of the only known beta subunit gene of phosphorylase kinase,PHKB, they are associated with a surprisingly mild clinical phenotype,affecting virtually only the liver, and relatively high residual enzymeactivity of approximately 10%.