Disease relevance of PHKG2

• Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis [1].
• 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 [1].
• Three patients with liver cirrhosis in childhood analyzed previously all had PHKG2 mutations [2].

High impact information on PHKG2

• We report here that autosomal liver-specific Phk deficiency is associated with mutations in the gene encoding the testis/liver isoform of the catalytic gamma subunit (PHKG2) [3].
• We found homozygous PHKG2 mutations in three human patients of consanguineous parentage and in the gsd (glycogen storage disease) rat strain, which is thus identified as an animal model for the human disorder [3].
• 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 [1].
• 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].
• 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 [1].

Biological context of PHKG2

• We conclude that liver phosphorylase kinase deficiency with a severe phenotype, with or without cirrhosis, is indeed often caused by PHKG2 mutations [2].
• This suggested that this genotype may generally cause a more severe clinical manifestation, but to date PHKG2 mutations have been identified in only seven patients [2].
• Two clones had homology to random partially sequenced cDNAs, one clone was likely to be a GRP78 pseudogene, one clone mapped the PHKG2 gene to 16p11.2-16p12.1, and one clone had homology to human S13 ribosomal protein [4].
• This putative protein kinase, given the preliminary designation "PSK-C3," is similar in primary structure to phosphorylase kinase catalytic subunit (PhK-gamma) isolated from rabbit skeletal muscle [5].

Anatomical context of PHKG2

• 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 [1].
• The level of similarity does not appear sufficient, however, to suggest that PSK-C3 represents the human homolog of skeletal muscle PhK-gamma [5].

References