HGNC Approved Gene Symbol: PHKG2
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:30,748,425-30,761,176 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Glycogen storage disease IXc | 613027 | Autosomal recessive | 3 |
The PHKG2 gene encodes the hepatic and testis isoform of the gamma subunit of phosphorylase kinase (PHK; EC 2.7.11.19). The skeletal muscle isoform of the gamma subunit is encoded by the PHKG1 gene (172470).
Whitmore et al. (1994) isolated a clone identified as the PHKG2 gene from a heteronuclear cDNA library constructed from a mouse/human somatic cell hybrid that contained chromosome 16. Most of the sequence showed 100% homology with the sequence of an isoform of a catalytic subunit of phosphorylase kinase (Hanks, 1989).
Burwinkel et al. (1998) determined that the PHKG2 gene contains 10 exons and spans 9.5 kb. The positions of introns were highly conserved between PHKG2 and PHKG1. The beginning of intron 2 harbors a highly polymorphic GGT/GT microsatellite repeat.
Whitmore et al. (1994) mapped the PHKG2 gene to chromosome 16p12.1-p11.2 by use of a high-resolution somatic cell panel.
Glycogen Storage Disease IXc
Maichele et al. (1996) reported that autosomal liver-specific PHK deficiency (glycogen storage disease IXc; GSD9C; 613027) was caused by mutations in the PHKG2 gene. They found homozygous PHKG2 mutations in 3 patients of consanguineous parentage. One mutation was a single basepair insertion in codon 89 that caused a frameshift and premature chain termination (172471.0001). The 3 other mutations resulted in nonconservative replacements of amino acid residues that are highly conserved within the catalytic core regions of all protein kinases. The findings suggested that the PHKG2 gene product is the predominant isoform of catalytic gamma subunit of PHK not only in testis but also in liver, erythrocytes, and possibly other nonmuscle tissues.
Burwinkel et al. (1998) identified homozygous translation-terminating mutations in the PHKG2 gene, R442X (172471.0004) and 277delC (172471.0005), in 2 patients with liver phosphorylase kinase deficiency who developed cirrhosis in childhood. As liver phosphorylase kinase deficiency is generally a benign condition and progression to cirrhosis is very rare, the findings suggested to the authors that PHKG2 mutations are particularly associated with an increased cirrhosis risk.
Burwinkel et al. (2000) reported compound heterozygosity for missense mutations in the PHKG2 gene (172471.0006; 172471.0007) in a child with phosphorylase kinase deficiency and cirrhosis.
Roscher et al. (2014) reported 3 novel mutations in the PHKG2 gene resulting in GSD IXc.
Associations Pending Confirmation
For discussion of a possible association between variation in the PHKG2 gene and Mauriac syndrome complicating type 1 diabetes, see 172471.0008.
Malthus et al. (1980) described deficiency of liver phosphorylase kinase in rats and concluded that it was an autosomal recessive trait. Apart from hepatomegaly, the affected rats appear healthy. Clark and Haynes (1988) described autosomal recessive glycogen storage disease in the rat (gsd/gsd). Maichele et al. (1996) identified a homozygous mutation in the rat Phkg2 gene (D215N) as responsible for the gsd phenotype in the rat.
Gibson et al. (2021) generated a Phkg2 knockout mouse model. Compared to wildtype mice, Phkg2 -/- mice had reduced body weight at 1 month of age, but similar weight at 2 or 3 months of age, and had significantly higher liver to body ratio. Liver tissue from the knockout mice had significantly elevated glycogen content, and liver histology demonstrated heterogeneously enlarged hepatocytes and evidence of early perisinusoidal liver fibrosis. Urine from knockout mice had elevated Hex-4, a biomarker of glycogen accumulation, and serum from knockout mice had elevated AST and ALT. Gibson et al. (2021) concluded that the Phkg2 -/- mice recapitulated the liver-specific glycogen accumulation phenotype of patients with glycogen storage disease IXc.
In a Norwegian girl with autosomal recessive glycogen storage disease IXc (GSD9C; 613027) Sovik et al. (1982), Maichele et al. (1996) identified homozygosity for a 1-bp insertion in codon 89 of the PHKG2 gene; the resultant frameshift (after 22% of the normal length of the reading frame) led to premature termination of the predicted polypeptide after 12 additional amino acids. The parents, who were fourth cousins, and a sister were unaffected. She proband presented at 5 months of age, and again at 3 years, with marked hepatomegaly, generalized muscular hypotonia, growth retardation, elevated serum transaminases, and massive liver glycogenosis. PHK activity was barely detectable in liver; in a muscle biopsy, PHK activity was moderately reduced (35% of controls) but muscle glycogen content was nevertheless low. No liver fibrosis was observed. She attained a normal height of 172 cm at age 18, and menarche was at age 17. The relative size of the liver gradually decreased, and at age 18 serum activities of gamma-glutamyltransferase and alanine aminotransferase were approaching normal ranges. Serum cholesterol was normal, hypoglycemic symptoms were not noted, and body weight was normal.
In a French girl with glycogen storage disease IXc (GSD9C; 613027), whose parents were first cousins, Maichele et al. (1996) identified homozygosity for a G-to-A transition in the PHKG2 gene that led to a gly189-to-glu (G189E) substitution. G189 is absolutely conserved between the testicular and muscle forms of the gamma subunit of several species and is never occupied by charged amino acids. The patient had been hospitalized at 7 months of age because of hypoglycemic episodes and pronounced hepatomegaly. Mild muscle hypotonia and retardation of growth and motor development were also observed. Notable laboratory findings were persistent hypoglycemia with acidosis, and elevated triglycerides and transaminases. Liver histology revealed fine portal fibrosis.
In a Pakistani girl with glycogen storage disease IXc (GSD9C; 613027), whose parents were first cousins, Maichele et al. (1996) demonstrated homozygosity for a val106-to-glu (V106E) missense mutation in the PHKG2 gene. The girl was admitted at the age of 15 months for investigation of a distended abdomen due to hepatomegaly with no other clinical symptoms except growth retardation. However, she had increased serum ALT and triglycerides, increased liver glycogen, and severe fibrosis and proliferation of bile ducts on liver biopsy.
In a female with liver phosphorylase kinase deficiency and cirrhosis (GSD9C; 612027), whose parents were consanguineous, Burwinkel et al. (1998) found point mutations in the PHKG2 gene. One patient had a C-to-T transition in exon 3, resulting in an arg44-to-ter (R44X) nonsense mutation. In an earlier biochemical analysis of her family (Kagalwalla et al., 1995), her father and 2 sibs had PHK activities in the heterozygous range, whereas her mother had normal PHK activity in repeated tests, so that a new maternal mutation was suspected in spite of her parents' consanguinity. However, analysis of the parents' DNA indicated that both were heterozygous for the nonsense mutation.
In a female with deficiency of liver phosphorylase kinase and cirrhosis (GSD9C; 613027) who had previously been described by Shiomi et al. (1989), Burwinkel et al. (1998) identified deletion of a cytosine residue in codon 93 (exon 4) of the PHKG2 gene, leading to a frameshift after 23% of the coding sequence and termination of translation after 17 additional codons. The patient's parents were consanguineous.
In a male child of unrelated English parents with liver phosphorylase kinase deficiency and cirrhosis (GSD9C; 613027), Burwinkel et al. (2000) identified compound heterozygosity for 2 mutations in the PHKG2 gene: a C-to-T transition resulting in a his144-to-tyr (H144Y) substitution, which was inherited from his father, and a T-to-G transversion resulting in a leu225-to-arg (L225R) substitution (172471.0007), which was inherited from his mother.
For discussion of the leu225-to-arg (L225R) mutation in the PHKG2 gene that was found in compound heterozygous state in a child with liver phosphorylase kinase deficiency and cirrhosis (GSD9C; 613027) by Burwinkel et al. (2000), see 172471.0006.
This variant is classified as a variant of unknown significance because its contribution to Mauriac syndrome complicating diabetes type 1 has not been confirmed.
Mauriac syndrome is a severe complication of type 1 diabetes that manifests as massive liver enlargement due to glycogen storage, growth failure, and delayed puberty. In an 18-year-old man with poorly controlled type 1 diabetes, who presented at age 13 years with Mauriac syndrome, MacDonald et al. (2016) identified heterozygosity for a G-A transition in exon 9 of the PHKG2 gene, resulting in an arg309-to-gln (R309Q) substitution at a conserved residue within domain N. The mutation was inherited from his unaffected mother, who did not have diabetes; his father, who died at 45 years of age from complications of poorly controlled type 1 diabetes but who had never exhibited an enlarged liver or growth failure, did not carry the mutation. The mutation was not found in 231 children with type 1 diabetes without hepatomegaly. Functional analysis in human liver cells demonstrated that the 50% presence of the R309Q mutant causes complete inhibition of PHK enzyme activity, consistent with a dominant-negative mechanism; the mutant cell line contained 33 to 70% higher glycogen levels than wildtype cells. MacDonald et al. (2016) concluded that the phenotype can be caused in patients with type 1 diabetes by mutation in the PHKG2 gene and possibly other glycogen metabolism enzyme genes, and suggested screening of additional patients.
Burwinkel, B., Shiomi, S., Al Zaben, A., Kilimann, M. W. Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. Hum. Molec. Genet. 7: 149-154, 1998. [PubMed: 9384616] [Full Text: https://doi.org/10.1093/hmg/7.1.149]
Burwinkel, B., Tanner, M. S., Kilimann, M. W. Phosphorylase kinase deficient liver glycogenosis: progression to cirrhosis in infancy associated with PHKG2 mutations (H144Y and L225R). (Letter) J. Med. Genet. 37: 376-377, 2000. [PubMed: 10905889] [Full Text: https://doi.org/10.1136/jmg.37.5.376]
Clark, D., Haynes, D. The glycogen storage disease (gsd/gsd) rat. Curr. Top. Cell. Regul. 29: 217-263, 1988. [PubMed: 3293925] [Full Text: https://doi.org/10.1016/b978-0-12-152829-4.50007-0]
Gibson, R. A., Lim, J.-A., Choi, S. J., Flores, L., Clinton, L., Bali, D., Young, S., Asokan, A., Sun, B., Kishnani, P. S. Characterization of liver GSD IX gamma-2 pathophysiology in a novel Phkg2 -/- mouse model. Molec. Genet. Metab. 133: 269-276, 2021. [PubMed: 34083142] [Full Text: https://doi.org/10.1016/j.ymgme.2021.05.008]
Hanks, S. K. Messenger ribonucleic acid encoding an apparent isoform of phosphorylase kinase catalytic subunit is abundant in the adult testis. Molec. Endocr. 3: 110-116, 1989. [PubMed: 2915644] [Full Text: https://doi.org/10.1210/mend-3-1-110]
Kagalwalla, A. F., Kagalwalla, Y. A., al Ajaji, S., Gorka, W., Ali, M. A. Phosphorylase b kinase deficiency glycogenosis with cirrhosis of the liver. J. Pediat. 127: 602-605, 1995. [PubMed: 7562285] [Full Text: https://doi.org/10.1016/s0022-3476(95)70123-0]
MacDonald, M. J., Hasan, N. M., Ansari, I. H., Longacre, M. J., Kendrick, M. A., Stoker, S. W. Discovery of a genetic metabolic cause for Mauriac syndrome in type 1 diabetes. Diabetes 65: 2051-2059, 2016. [PubMed: 27207549] [Full Text: https://doi.org/10.2337/db16-0099]
Maichele, A. J., Burwinkel, B., Maire, I., Sovik, O., Kilimann, M. W. Mutations in the testis/liver isoform of the phosphorylase kinase gamma subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans. Nature Genet. 14: 337-340, 1996. [PubMed: 8896567] [Full Text: https://doi.org/10.1038/ng1196-337]
Malthus, R., Clark, D. G., Watts, C., Sneyd, J. G. T. Glycogen-storage disease in rats, a genetically determined deficiency of liver phosphorylase kinase. Biochem. J. 188: 99-106, 1980. [PubMed: 6931596] [Full Text: https://doi.org/10.1042/bj1880099]
Roscher, A., Patel, J., Hewson, S., Nagy, L., Feigenbaum, A., Kronick, J., Raiman, J., Schulze, A., Siriwardena, K., Mercimek-Mahmutoglu, S. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Molec. Genet. Metab. 113: 171-176, 2014. [PubMed: 25266922] [Full Text: https://doi.org/10.1016/j.ymgme.2014.09.005]
Shiomi, S., Saeki, Y., Kim. K., Nishiguchi, S., Seki, S., Kuroki, T., Kobayashi, K., Harihara, S., Owada, M. A female case of type VIII glycogenosis who developed cirrhosis of the liver and hepatocellular tumor. Gastroent. Jpn. 24: 711-714, 1989. [PubMed: 2558039] [Full Text: https://doi.org/10.1007/BF02774172]
Sovik, O., deBarsy, T., Maehle, B. Phosphorylase kinase deficiency: severe glycogen storage disease with evidence of autosomal recessive mode of inheritance. (Letter) Europ. J. Pediat. 139: 210 only, 1982. [PubMed: 6962066] [Full Text: https://doi.org/10.1007/BF01377363]
Whitmore, S. A., Apostolou, S., Lane, S., Nancarrow, J. K., Phillips, H. A., Richards, R. I., Sutherland, G. R., Callen, D. F. Isolation and characterization of transcribed sequences from a chromosome 16 hn-cDNA library and the physical mapping of genes and transcribed sequences using a high-resolution somatic cell panel of human chromosome 16. Genomics 20: 169-175, 1994. [PubMed: 8020963] [Full Text: https://doi.org/10.1006/geno.1994.1150]