Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical phenotype in blood cells associated with a missense mutation in the beta subunit gene (PHKB).

We have identified mutations in the phosphorylase kinase (Phk) beta subunit gene in a male patient with liver glycogenosis caused by Phk deficiency. The patient's DNA has been analyzed for mutations in the genes encoding the alpha L, beta, and gamma TL subunits of Phk, all of which can be responsible for liver glycogenosis, by a strategy primarily based on reverse transcription/polymerase chain reaction of blood RNA and complemented by analysis of genomic DNA. His alpha L and gamma TL coding sequences are normal, whereas he is compound-heterozygous for two mutations in the beta subunit gene, PHKB. The first is a splice-site mutation (IVS4 [-2A-->G]) causing the reading-frame-disrupting deletion of exon 5 in the mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon 5. This is the first missense mutation identified in PHKB, as opposed to nine translation-terminating mutations described to date. It offers an explanation for the unique biochemical phenotype of this patient. In his leukocytes, low Phk activity is measured when tested with the endogenous liver isoform of phosphorylase as the protein substrate, but normal activity is observed when tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his erythrocytes is low with both substrates. The missense mutation may selectively impair the interaction of Phk with one isoform of its substrate protein and may destabilize the enzyme in a cell-type-specific way. This phenotype shares some aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising from missense mutations in the alpha L subunit gene (PHKA2), but differs from XLG2 in other respects. The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types. Moreover, it emphasizes that missense mutations in Phk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.