LIVER GLYCOGENOSIS DUE TO PHOSPHORYLASE-KINASE DEFICIENCY - PHKG2 GENE STRUCTURE AND MUTATIONS ASSOCIATED WITH CIRRHOSIS

Mutations in three different genes of phosphorylase kinase (Phk) subun its, PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the liver, The autosomal-recessive, liver-specific variant of Phk d eficiency 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 huma n PHKG2 gene, The gene extends over 9.5 kilonucleotides and is divided into 10 exons; positions of introns are highly conserved between PHKG 2 and the gene of the muscle isoform of the gamma subunit, PHKG1. The beginning of intron 2 harbors a highly informative GGT/GT microsatelli te repeat, the first polymorphic marker in the PHKG2 gene at human chr omosome 16p11.2-p12.1. Employing the gene sequence, we have identified homozygous translation-terminating mutations, 277delC and Arg44ter, i n the two published cases of liver Phk deficiency who developed cirrho sis in childhood, As liver Phk deficiency is generally a benign condit ion and progression to cirrhosis is very rare, this finding suggests t hat PHKG2 mutations are associated with an increased cirrhosis risk.