Mutations in three different genes of
phosphorylase kinase (Phk) subunits, PHKA2, PHKB and PHKG2, can give rise to
glycogen storage disease of the liver. The autosomal-recessive, liver-specific variant of
Phk deficiency is caused by mutations in the gene encoding the testis/liver
isoform of the catalytic gamma subunit, PHKG2. To facilitate mutation detection and to improve our understanding of the molecular evolution of Phk subunit
isoforms, we have determined the structure of the human PHKG2 gene. The gene extends over 9.5 kilonucleotides and is divided into 10 exons; positions of introns are highly conserved between PHKG2 and the gene of the muscle
isoform of the gamma subunit, PHKG1. The beginning of intron 2 harbors a highly informative GGT/GT microsatellite repeat, the first polymorphic marker in the PHKG2 gene at human chromosome 16p11.2-p12.1. Employing the gene sequence, we have identified homozygous translation-terminating mutations, 277delC and Arg44ter, in the two published cases of liver
Phk deficiency who developed
cirrhosis in childhood. As liver
Phk deficiency is generally a benign condition and progression to
cirrhosis is very rare, this finding suggests that PHKG2 mutations are associated with an increased
cirrhosis risk.