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 su bunit gene in a male patient with liver glycogenosis caused by Phk def iciency. The patient's DNA has been analyzed for mutations in the gene s encoding the alpha(L), beta, and gamma(TL) subunits of Phk, all of w hich can be responsible for liver glycogenosis, by a strategy primaril y based on reverse transcription/polymerase chain reaction of blood RN A and complemented by analysis of mic DNA. His alpha(L) and gamma(TL) coding sequences are normal, whereas he is compound-heterozygous for t wo mutations in the beta subunit gene, PHKB. The first is a splice-sit e mutation (IVS4 [-2A-->G]) causing the reading-frame-disrupting delet ion 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 mutatio n identified in PHKB, as opposed to nine translation-terminating mutat ions described to date. It offers an explanation for the unique bioche mical phenotype of this patient. In his leukocytes, low Phk activity i s measured when tested with the endogenous liver isoform of phosphoryl ase as the protein substrate, but normal activity is observed when tes ted with muscle phosphorylase added in vitro. In contrast, Phk activit y in his erythrocytes is low with both substrates. The missense mutati on may selectively impair the interaction of Phk with one isoform of i ts substrate protein and may destabilize the enzyme in a cell-type-spe cific way. This phenotype shares some aspects with X-linked liver glyc ogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising f rom missense mutations in the alpha(L) subunit gene (PHKA2), but diffe rs from XLG2 in other respects. The present case demonstrates that mut ations in Phk genes other than PHKA2, can also be associated with unty pically high activity in certain blood cell types. Moreover, it emphas izes that missense mutations in Phk: may cause unusual patterns of tis sue involvement that would not be predicted a priori from the tissue s pecificity of expression of the mutated gene sequences.