HGNC Approved Gene Symbol: PHKA1
SNOMEDCT: 819953000;
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38) : X:72,578,814-72,714,306 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Muscle glycogenosis | 300559 | X-linked recessive | 3 |
The PHKA1 gene encodes the alpha subunit of muscle phosphorylase kinase (EC 2.7.1.38), a key regulatory enzyme of glycogen metabolism. Phosphorylase kinase consists of 4 copies of an alpha-beta-gamma-delta tetramer. The alpha, beta (PHKB; 172490), and gamma (PHKG1; 172470 and PHKG2; 172471) subunits have several isoforms; the delta subunit is calmodulin (CALM1; 114180). PHKA2 (306000) encodes the alpha subunit of liver-specific phosphorylase kinase and is located on the X chromosome.
Zander et al. (1988) isolated and sequenced a cDNA clone for rabbit Phka1 from fast-twitch skeletal muscle. The deduced 1,237-residue protein had a molecular mass of 138 Da. Seven putative serine phosphorylation sites could be identified. Northern blot analysis identified 2 mRNA transcripts.
Wullrich et al. (1993) isolated a cDNA corresponding to muscle phosphorylase kinase from a human skeletal muscle cDNA library. The deduced amino acid sequence shows 96% identity to the rabbit protein, but lacks a major part of its multiphosphorylation domain, including the main phosphorylation domain for cAMP-dependent protein kinase A (PKA; 601639). Analysis of this region by RT-PCR showed that it is subject to alternative mRNA splicing. The expression of the differentially spliced PHKA1 subtypes differed markedly between corresponding human and rabbit tissues.
Buckle et al. (1985) studied the regional mapping of genes on the mouse X chromosome, including Phka, the mouse homolog for the human muscle phosphorylase kinase gene, and predicted that the human gene may be situated near the centromere. Ryder-Cook et al. (1989) and Barnard et al. (1990) mapped the Phka locus in the mouse distal to Zfx and proximal to Pgk1 by interspecific linkage analysis. Phka appeared to be very close to the Pgk1 locus. They predicted that the corresponding gene in man should be centromeric and close to PGK (311800) on Xq13.
By study of somatic cell hybrids and by in situ chromosomal hybridization using rabbit muscle cDNAs, Francke et al. (1989) mapped 2 of the 4 subunits that comprise muscle phosphorylase kinase: the alpha subunit to Xq12-q13 and the beta subunit to 16q12-q13.
Lafreniere et al. (1993) showed that the PHKA1 gene is in the same 2.6-Mb segment as RPS4X (312760) and XIST (314670) in Xq13. Furthermore, they showed that the transcriptional orientation of the gene is cen--3-prime--PHKA1--5-prime--qter.
In a patient with, glycogen storage disease type IXd (GSD9D; 300559), also known as X-linked muscle phosphorylase kinase deficiency (Clemens et al., 1990), Wehner et al. (1994) identified a nonsense mutation in the PHKA1 gene (311870.0001). The findings confirmed that the condition in this patient was a human homolog of the X-linked muscle Phk deficiency of the I-strain mouse (Schneider et al., 1993). In a second patient with muscle phosphorylase kinase deficiency reported by Clemens et al. (1990), Burwinkel et al. (2003) identified a missense mutation in the PHKA1 gene (311870.0003).
Bruno et al. (1998) reported a splice-junction mutation in the PHKA1 gene (311870.0002) in a 28-year old Caucasian male with exercise intolerance, myoglobinuria, and muscle PHK deficiency.
Lyon et al. (1967) found an X-linked codominant electrophoretic polymorphism of muscle phosphorylase b kinase in the mouse.
Davidson et al. (1992) presented evidence that the murine equivalent of the PHKA1 gene is mutant in the I-strain of mice with myopathy. Schneider et al. (1993) described the first specific mutation responsible for any form of PHK deficiency: a single-nucleotide insertion in the coding sequence of the alpha-1 subunit muscle isozyme in the I-strain mouse.
In a patient with glycogen storage disease IXd (GSD9D; 300559) reported by Clemens et al. (1990), Wehner et al. (1994) identified a nonsense mutation, glu1112-to-ter (E1112X), in the PHKA1 gene. The PHK activity was only 0.3% of normal in muscle, but showed normal levels in red blood cells and liver. Histologically, mild glycogenosis with subsarcolemmal accumulations of glycogen and focal muscle fiber necrosis were observed. The patient's mother, who died at the age of about 26 years, and his daughter, aged 33 at the time of the report, were reportedly asymptomatic.
In a 28-year-old man with muscle phosphorylase kinase deficiency (GSD9D; 300559), Bruno et al. (1998) identified a G-to-C transversion at the 5-prime end of an intron (referred to as 'intron L' by them) in the PHKA1 gene. The mutation destroys the highly conserved GT sequence at the 5-prime splice junction of the intron, which resulted in skipping of the preceding 201-bp exon. The patient, reported as patient 1 of Wilkinson et al. (1994), had been diagnosed with PHK deficiency at age 15.
In a patient with muscle phosphorylase kinase deficiency (GSD9D; 300559) reported by Clemens et al. (1990), Burwinkel et al. (2003) identified an 896A-T transversion in the PHKA1 gene, resulting in an asp299-to-val (D299V) substitution in a highly conserved region of the protein. Muscle biopsy showed increased subsarcolemmal glycogen accumulation. Total phosphorylase was normal in muscle, and PhK activity was markedly reduced in muscle but normal in red blood cells.
In a patient with muscle phosphorylase kinase deficiency (GSD9D; 300559) who had onset of symptoms at age 43 years, Wuyts et al. (2005) identified a 1-bp deletion, 695delC, in exon 7 of the PHKA1 gene, resulting in a frameshift and premature termination of the protein at amino acid position 242. The mutated protein was predicted to lack the multiphosphorylation domain located in the last 300 residues of the protein, thus rendering it nonfunctional.
Preisler et al. (2012) identified a 695delC mutation in a 69-year-old man with GSD IXd who had persistently raised levels of creatine kinase after treatment with statin therapy. He had worked in the military, and neurologic and EMG examination at age 64 were normal. Muscle biopsy showed increased glycogen and PHK activity was less than 11% of normal. Ischemic forearm exercise test was essentially similar to control, except for an increase in plasma ammonia. In contrast, aerobic exercise resulted in a blunted lactate response compared to controls, suggesting a mild impairment in muscle glycogenolysis. Preisler et al. (2012) suggested that high exercise intensity may activate myophosphorylase (PYGM; 608455) in patients with PHK deficiency, thus preserving some glycogenolysis in these patients.
In a 50-year-old man with muscle phosphorylase kinase deficiency (GSD9D; 300559), Orngreen et al. (2008) identified an 831G-A transition in exon 7 of the PHKA1 gene, resulting in a gly223-to-arg (G223R) substitution. The patient reported progressive exercise intolerance, muscle stiffness on exercise, and nighttime muscle cramps since childhood. Serum creatine kinase levels were mildly elevated on several occasions, and there was low muscle PHK activity and high muscle glycogen content.
Barnard, P. J., Derry, J. M. J., Ryder-Cook, A. S., Zander, N. F., Kilimann, M. W. Mapping of the phosphorylase kinase alpha subunit gene on the mouse X chromosome. Cytogenet. Cell Genet. 53: 91-94, 1990. [PubMed: 1973380] [Full Text: https://doi.org/10.1159/000132902]
Bruno, C., Manfredi, G., Andreu, A. L., Shanske, S., Krishna, S., Ilse, W. K., DiMauro, S. A splice junction mutation in the alpha-M gene of phosphorylase kinase in a patient with myopathy. Biochem. Biophys. Res. Commun. 249: 648-651, 1998. [PubMed: 9731190] [Full Text: https://doi.org/10.1006/bbrc.1998.9211]
Buckle, V. J., Edwards, J. H., Evans, E. P., Jonasson, J. A., Lyon, M. F., Peters, J., Searle, A. G. Comparative maps of human and mouse X chromosomes. (Abstract) Cytogenet. Cell Genet. 40: 594-595, 1985.
Burwinkel, B., Hu, B., Schroers, A., Clemens, P. R., Moses, S. W., Shin, Y. S., Pongratz, D., Vorgerd, M., Kilimann, M. W. Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. Europ. J. Hum. Genet. 11: 516-526, 2003. [PubMed: 12825073] [Full Text: https://doi.org/10.1038/sj.ejhg.5200996]
Clemens, P. R., Yamamoto, M., Engel, A. G. Adult phosphorylase b kinase deficiency. Ann. Neurol. 28: 529-538, 1990. [PubMed: 2252364] [Full Text: https://doi.org/10.1002/ana.410280410]
Davidson, J. J., Ozcelik, T., Hamacher, C., Willems, P. J., Francke, U., Kilimann, M. W. 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. Proc. Nat. Acad. Sci. 89: 2096-2100, 1992. [PubMed: 1372435] [Full Text: https://doi.org/10.1073/pnas.89.6.2096]
Francke, U., Darras, B. T., Zander, N. F., Kilimann, M. W. Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13. Am. J. Hum. Genet. 45: 276-282, 1989. [PubMed: 2757032]
Lafreniere, R. G., Brown, C. J., Rider, S., Chelly, J., Taillon-Miller, P., Chinault, A. C., Monaco, A. P., Willard, H. F. 2.6 Mb YAC contig of the human X inactivation center region in Xq13: physical linkage of the RPS4X, PHKA1, XIST and DXS128E genes. Hum. Molec. Genet. 2: 1105-1115, 1993. [PubMed: 8401491] [Full Text: https://doi.org/10.1093/hmg/2.8.1105]
Lyon, J. B., Jr., Porter, J., Robertson, M. Phosphorylase B kinase inheritance in mice. Science 155: 1550-1551, 1967. [PubMed: 6020474] [Full Text: https://doi.org/10.1126/science.155.3769.1550]
Orngreen, M. C., Schelhaas, H. J., Jeppesen, T. D., Akman, H. O., Wevers, R. A., Andersen, S. T., ter Laak, H. J., van Diggelen, O. P., DiMauro, S., Vissing, J. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology 70: 1876-1882, 2008. [PubMed: 18401027] [Full Text: https://doi.org/10.1212/01.wnl.0000289190.66955.67]
Preisler, N., Orngreen, M. C., Echaniz-Laguna, A., Laforet, P., Lonsdorfer-Wolf, E., Doutreleau, S., Geny, B., Akman, H.O., DiMauro, S., Vissing, J. Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease? Neurology 78: 265-268, 2012. [PubMed: 22238410] [Full Text: https://doi.org/10.1212/WNL.0b013e31824365f9]
Ryder-Cook, A. S., Derry, J. M. J., Barnard, P. J. Localization of the phosphorylase kinase alpha subunit gene on the mouse X chromosome. (Abstract) Cytogenet. Cell Genet. 51: 1071-1072, 1989.
Schneider, A., Davidson, J. J., Wullrich, A., Kilimann, M. W. Phosphorylase kinase deficiency in I-strain mice is associated with a frameshift mutation in the alpha-subunit muscle isoform. Nature Genet. 5: 381-385, 1993. [PubMed: 8298647] [Full Text: https://doi.org/10.1038/ng1293-381]
Wehner, M., Clemens, P. R., Engel, A. G., Kilimann, M. W. Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the alpha subunit. Hum. Molec. Genet. 3: 1983-1987, 1994. [PubMed: 7874115] [Full Text: https://doi.org/10.1093/hmg/3.11.1983]
Wilkinson, D. A., Tonin, P., Shanske, S., Lombes, A., Carlson, G. M., DiMauro, S. Clinical and biochemical features of 10 adult patients with muscle phosphorylase kinase deficiency. Neurology 44: 461-466, 1994. [PubMed: 8145916] [Full Text: https://doi.org/10.1212/wnl.44.3_part_1.461]
Wullrich, A., Hamacher, C., Schneider, A., Kilimann, M. W. The multiphosphorylation domain of the phosphorylase kinase alpha-M and alpha-L subunits is a hotspot of differential mRNA processing and of molecular evolution. J. Biol. Chem. 268: 23208-23214, 1993. [PubMed: 8226841]
Wuyts, W., Reyniers, E., Ceuterick, C., Storm, K., de Barsy, T., Martin, J.-J. Myopathy and phosphorylase kinase deficiency caused by a mutation in the PHKA1 gene. Am. J. Med. Genet. 133A: 82-84, 2005. [PubMed: 15637709] [Full Text: https://doi.org/10.1002/ajmg.a.30517]
Zander, N. F., Meyer, H. E., Hoffmann-Posorske, E., Crabb, J. W., Heilmeyer, L. M. G., Jr., Kilimann, M. W. cDNA cloning and complete primary structure of skeletal muscle phosphorylase kinase (alpha subunit). Proc. Nat. Acad. Sci. 85: 2929-2933, 1988. [PubMed: 3362857] [Full Text: https://doi.org/10.1073/pnas.85.9.2929]