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Gene Review

PHKA2  -  phosphorylase kinase, alpha 2 (liver)

Homo sapiens

Synonyms: GSD9A, PHK, PHKLA, PYK, PYKL, ...
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Disease relevance of PHKA2


High impact information on PHKA2

  • The catalytic core of PHK exists as a dimer in crystals of the ternary complex, and the relevance of this phenomenon to its in vivo recognition of dimeric glycogen phosphorylase b is considered [5].
  • This anchoring of the main chain of the substrate peptide at a fixed distance from the gamma-phosphate of ATP explains the selectivity of PHK for serine/threonine over tyrosine as a substrate [5].
  • Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II [6].
  • By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations [6].
  • XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver [6].

Biological context of PHKA2

  • Although missense, nonsense and splicesite mutations in the PHKA2 gene were recently identified in several cases of XLG1, no mutations have yet been described for XLG2 and a molecular explanation for the peculiar biochemical phenotype of XLG2 has been lacking [7].
  • A missense mutation replacing arginine at amino acid position 186 by histidine (R186H) was identified in the PHKA2 gene [8].
  • We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations [3].
  • These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK [3].
  • In this study we identified four point mutations in four unrelated XLG I patients: three mutations introduce a premature stop codon, whereas the fourth mutation abolishes a splice site consensus sequence leading to exon skipping [9].

Anatomical context of PHKA2

  • Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2) [7].
  • One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes [10].
  • However, in contrast to patients with XLG, the patients described here have no reduced phosphorylase kinase activity in erythrocytes and leukocytes, and no enzyme deficiency could be found [11].
  • Gi1 alpha was expressed selectively in a pre-T cell line, P30/PHK among lymphoid-lineage cell lines and a myeloblastic cell line, KG-1 among myelomonocytoid cell lines [12].

Associations of PHKA2 with chemical compounds


Other interactions of PHKA2

  • Mutations in three different genes of phosphorylase kinase (Phk) subunits, PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the liver [17].
  • YAC contig construction allowed the following locus order to be established: Xpter-DXS16-DXS69E-DXS414-XE59 - DXS9 - (GLRA2, DXS987) - (PIGA, DXS207) - DXS1053-DXS197-(GRPR,DXS43)-CALB3-DXS14 16- DXS1317 - DXS1195 - DXS418 - DXS257 - (PHKA2, DXS999)-DXS443-DXS1229-Xcen [18].
  • In contrast to the muscle isoform gene, PHKA1, the gene of this additional isoform, PHKA2, is predominantly expressed in liver and other nonmuscle tissues [1].
  • X-linked mutations leading to PHK deficiency, known to exist in humans and mice, are likely to involve this locus [19].

Analytical, diagnostic and therapeutic context of PHKA2


  1. cDNA cloning of a liver isoform of the phosphorylase kinase alpha subunit and mapping of the gene to Xp22.2-p22.1, the region of human X-linked liver glycogenosis. Davidson, J.J., Ozçelik, T., Hamacher, C., Willems, P.J., Francke, U., Kilimann, M.W. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  2. X-linked liver glycogenosis: localization and isolation of a candidate gene. Hendrickx, J., Coucke, P., Bossuyt, P., Wauters, J., Raeymaekers, P., Marchau, F., Smit, G.P., Stolte, I., Sardharwalla, I.B., Berthelot, J. Hum. Mol. Genet. (1993) [Pubmed]
  3. X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase. Hendrickx, J., Dams, E., Coucke, P., Lee, P., Fernandes, J., Willems, P.J. Hum. Mol. Genet. (1996) [Pubmed]
  4. Allergic reactions to Japanese encephalitis vaccine. Plesner, A.M. Immunology and allergy clinics of North America. (2003) [Pubmed]
  5. The crystal structure of a phosphorylase kinase peptide substrate complex: kinase substrate recognition. Lowe, E.D., Noble, M.E., Skamnaki, V.T., Oikonomakos, N.G., Owen, D.J., Johnson, L.N. EMBO J. (1997) [Pubmed]
  6. Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II. Hendrickx, J., Lee, P., Keating, J.P., Carton, D., Sardharwalla, I.B., Tuchman, M., Baussan, C., Willems, P.J. Am. J. Hum. Genet. (1999) [Pubmed]
  7. Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2). Burwinkel, B., Shin, Y.S., Bakker, H.D., Deutsch, J., Lozano, M.J., Maire, I., Kilimann, M.W. Hum. Mol. Genet. (1996) [Pubmed]
  8. Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years. Hendrickx, J., Bosshard, N.U., Willems, P., Gitzelmann, R. Eur. J. Pediatr. (1998) [Pubmed]
  9. Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease. Hendrickx, J., Coucke, P., Dams, E., Lee, P., Odièvre, M., Corbeel, L., Fernandes, J.F., Willems, P.J. Hum. Mol. Genet. (1995) [Pubmed]
  10. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Burwinkel, B., Amat, L., Gray, R.G., Matsuo, N., Muroya, K., Narisawa, K., Sokol, R.J., Vilaseca, M.A., Kilimann, M.W. Hum. Genet. (1998) [Pubmed]
  11. Localization of a new type of X-linked liver glycogenosis to the chromosomal region Xp22 containing the liver alpha-subunit of phosphorylase kinase (PHKA2). Hendrickx, J., Coucke, P., Hors-Cayla, M.C., Smit, G.P., Shin, Y.S., Deutsch, J., Smeitink, J., Berger, R., Lee, P., Fernandes, J. Genomics (1994) [Pubmed]
  12. Analysis of the expression of seven G protein alpha subunit genes in hematopoietic cells. Matsuoka, M., Kaziro, Y., Asano, S., Ogata, E. Am. J. Med. Sci. (1993) [Pubmed]
  13. Isolation of cDNA encoding the human liver phosphorylase kinase alpha subunit (PHKA2) and identification of a missense mutation of the PHKA2 gene in a family with liver phosphorylase kinase deficiency. Hirono, H., Hayasaka, K., Sato, W., Takahashi, T., Takada, G. Biochem. Mol. Biol. Int. (1995) [Pubmed]
  14. Pharmacokinetics of ketorolac and p-hydroxyketorolac following oral and intramuscular administration of ketorolac tromethamine. Jung, D., Mroszczak, E.J., Wu, A., Ling, T.L., Sevelius, H., Bynum, L. Pharm. Res. (1989) [Pubmed]
  15. Ketorolac tromethamine pharmacokinetics and metabolism after intravenous, intramuscular, and oral administration in humans and animals. Mroszczak, E.J., Jung, D., Yee, J., Bynum, L., Sevelius, H., Massey, I. Pharmacotherapy (1990) [Pubmed]
  16. Plasma, urinary and fecal potassium changes in athletes during ambulatory, periodic, and continuous hypokinetic conditions. Zorbas, Y.G., Kakurin, V.J., Afonin, V.B., Charapakhin, K.P., Yarullin, V.L., Deogenov, V.A. Clin. Biochem. (2000) [Pubmed]
  17. Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. Burwinkel, B., Shiomi, S., Al Zaben, A., Kilimann, M.W. Hum. Mol. Genet. (1998) [Pubmed]
  18. A 6-Mb YAC contig in Xp22.1-p22.2 spanning the DXS69E, XE59, GLRA2, PIGA, GRPR, CALB3, and PHKA2 genes. Alitalo, T., Francis, F., Kere, J., Lehrach, H., Schlessinger, D., Willard, H.F. Genomics (1995) [Pubmed]
  19. Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13. Francke, U., Darras, B.T., Zander, N.F., Kilimann, M.W. Am. J. Hum. Genet. (1989) [Pubmed]
  20. Detection of PHKA2 gene mutation in four Japanese patients with hepatic phosphorylase kinase deficiency. Ban, K., Sugiyama, K., Goto, K., Mizutani, F., Togari, H. Tohoku J. Exp. Med. (2003) [Pubmed]
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