HGNC Approved Gene Symbol: PHKB
SNOMEDCT: 860860004;
Cytogenetic location: 16q12.1 Genomic coordinates (GRCh38) : 16:47,461,299-47,701,523 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q12.1 | Phosphorylase kinase deficiency of liver and muscle, autosomal recessive | 261750 | Autosomal recessive | 3 |
The PHKB gene encodes the beta subunit of phosphorylase kinase (PHK; EC 2.7.11.19). Phosphorylase kinase is a hexadecameric enzyme comprising 4 copies each of 4 unique subunits encoded by 4 different genes: alpha (PHKA1 (311870) and PHKA2 (300798), the skeletal muscle and hepatic isoforms, respectively); beta (PHKB); gamma (PHKG1 (172470) and PHKG2 (172471), the skeletal muscle and hepatic isoforms, respectively); and delta. The delta subunit can be encoded by 3 different genes (CALM1, 114180, CALM2, 114182, or CALM3, 114183). The beta subunit is the same in both the muscle and hepatic isoforms. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit, which encodes calmodulin, mediates the dependence of the enzyme on calcium concentration (Beauchamp et al., 2007).
Kilimann et al. (1988) and Zander et al. (1988) cloned DNA sequences encoding the alpha and beta PHK subunits from a rabbit muscle cDNA library. The deduced alpha and beta polypeptides are 1,237 and 1,092 amino acids long, respectively, and contain extensive regions of sequence homology.
Wullrich-Schmoll and Kilimann (1996) cloned the human PHKB gene and found that the deduced protein shares 95% amino acid sequence identity with the rabbit protein.
Wullrich-Schmoll and Kilimann (1996) determined that the PHKB gene contains 33 exons and spans at least 140 kb. Exons 26 and 27 are 2 homologous, mutually exclusively spliced exons in the middle of the gene; exon 2 is a facultatively utilized cassette exon encoding an alternative N terminus of the beta-subunit.
By Southern blot analysis of rodent-human somatic cell hybrids and by in situ hybridization, Francke et al. (1989) mapped the human PHKB gene to chromosome 16q12-q13.
Wullrich-Schmoll and Kilimann (1996) confirmed location of the PHKB gene to chromosome 16 by screening of a chromosome 16-specific genomic library. Two processed pseudogenes were identified.
In 1 female and 4 male patients with glycogen storage disease IXb (GSD9B; 261750) and PHK deficiency in both liver and muscle, Burwinkel et al. (1997) identified biallelic mutations in the PHKB gene. There were 5 different nonsense mutations (see, e.g., 172490.0002), a 1-bp insertion (172490.0001), a splice site mutation, and a large deletion involving the loss of exon 8. Although the mutations disrupted translation severely and occurred in constitutively expressed sequences of the only known beta-subunit gene of phosphorylase kinase, they were associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and with a relatively high residual enzyme activity of approximately 10%. Inheritance was autosomal recessive.
Roscher et al. (2014) reported 2 novel mutations in the PHKB gene resulting in GSD IXb.
In a patient with glycogen storage disease IXb (GSD9B; 261750), Burwinkel et al. (1997) identified compound heterozygosity for 2 mutations in the PHKB gene. On 1 allele, a stretch of 7 A residues in exon 14 was extended by an additional A, resulting in a frameshift in codon 421 and translation termination at the following triplet; on the other allele, a C-to-T transition in exon 21 resulted in a gln656-to-ter (Q656X; 172490.0002) substitution. Studies in the parents indicated that the frameshift mutation had been inherited from the father and the nonsense mutation from the mother. The patient was the only child of unrelated, healthy German parents and presented at the age of 22 months because of distended abdomen due to hepatomegaly. At the age of 4 years, the child had a height at the tenth percentile and weight at the fiftieth percentile, hepatomegaly, and a tendency to develop hypoglycemic symptoms after several hours of fasting or physical activity. There were no clinical indications of muscle involvement.
For discussion of the gln656-to-ter (Q656X) mutation in the PHKB gene that was found in compound heterozygous state in a patient with glycogen storage disease IXb (GSD9B; 261750) by Burwinkel et al. (1997), see 172490.0001.
In a Norwegian boy with glycogen storage disease type IXb (GSD9B; 261750), Burwinkel et al. (1997) identified compound heterozygosity for 2 mutations in the PHKB gene: a tyr418-to-ter (Y418X) substitution, and a double mutation, glu975-to-ter (E975X) and tyr974-to-his (Y974H) (172490.0004). The patient and his affected sister were children of unaffected, unrelated parents. They came to medical attention as infants because of hepatomegaly; glucagon response was normal in both (Lederer et al., 1975). Residual phosphorylase kinase activities were 18% of normal in red cell hemolysis of both, 5% in liver of the sister, and 0 to 13% (depending on pH) in muscle of the male. At the age of approximately 25, both patients were fully capable of everyday physical activities, but tended to develop hypoglycemic symptoms upon activity or fasting that were ameliorated by carbohydrate intake. Hepatomegaly had receded; clinical muscle symptoms had never been noted. RT-PCR analysis of RNA from both parents did not yield significant sequence signals for any of the 3 mutations in these sibs. As translation-terminating mutations often result in reduced abundance of the mRNA, Burwinkel et al. (1997) suspected that this might also be the case for both mutant alleles in this family, so that they would be detectable together in the patient but missed against the background of the higher levels of mRNA from the normal alleles in the parents. In genomic DNA they indeed could identify the Y418X mutation in the father and the double mutation in the mother.
For discussion of the tyr974-to-his (Y974H) and glu975-to-ter (E975X) double mutation in the PHKB gene that was found in compound heterozygous state in a patient with glycogen storage disease type IXb (GSD9B; 261750) by Burwinkel et al. (1997), see 172490.0003.
In a patient with glycogen storage disease type IXb (GSD9B; 261750), Burwinkel et al. (1997) found compound heterozygosity for 2 mutations in the PHKB gene: a splice site mutation, IVS4AS-2 A-to-G (172490.0006), causing a reading frame-disrupting deletion of exon 5 in the mRNA, and an ala117-to-pro (A117P) missense mutation, also in exon 5. They stated that this was the first missense mutation identified in PHKB; 9 translation-terminating mutations had been described to that time. The patient was a 22-month-old child of North African-Jewish heritage with hepatomegaly and slightly disturbed liver function tests.
For discussion of the splice site mutation in the PHKB gene (IVS4AS-2 A-to-G) that was found in compound heterozygous state in a patient with glycogen storage disease type IXb (GSD9B; 261750) by Burwinkel et al. (1997), see 172490.0005.
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Beauchamp, N. J., Dalton, A., Ramaswami, U., Niinikoski, H., Mention, K., Kenny, P., Kolho, K.-L., Raiman, J., Walter, J., Treacy, E., Tanner, S., Sharrard, M. Glycogen storage disease type IX: high variability in clinical phenotype. Molec. Genet. Metab. 92: 88-99, 2007. [PubMed: 17689125] [Full Text: https://doi.org/10.1016/j.ymgme.2007.06.007]
Burwinkel, B., Maichele, A. J., Aagenaes, O., Bakker, H. D., Lerner, A., Shin, Y. S., Strachan, J. A., Kilimann, M. W. Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB). Hum. Molec. Genet. 6: 1109-1115, 1997. [PubMed: 9215682] [Full Text: https://doi.org/10.1093/hmg/6.7.1109]
Burwinkel, B., Moses, S. W., Kilimann, M. W. Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical phenotype in blood cells associated with a missense mutation in the beta subunit gene (PHKB). Hum. Genet. 101: 170-174, 1997. [PubMed: 9402963] [Full Text: https://doi.org/10.1007/s004390050608]
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]
Kilimann, M. W., Zander, N. F., Kuhn, C. C., Crabb, J. W., Meyer, H. E., Heilmeyer, L. M. G., Jr. The alpha and beta subunits of phosphorylase kinase are homologous: cDNA cloning and primary structure of the beta subunit. Proc. Nat. Acad. Sci. 85: 9381-9385, 1988. [PubMed: 3200826] [Full Text: https://doi.org/10.1073/pnas.85.24.9381]
Lederer, B., Van Hoof, F., Van den Berghe, G., Hers, H. G. Glycogen phosphorylase and its converter enzymes in haemolysates of normal human subjects and of patients with type VI glycogen storage disease: a study of phosphorylase kinase deficiency. Biochem. J. 147: 23-35, 1975. [PubMed: 168880] [Full Text: https://doi.org/10.1042/bj1470023]
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]
Wullrich-Schmoll, A., Kilimann, M. W. Structure of the human gene encoding the phosphorylase kinase beta subunit (PHKB). Europ. J. Biochem. 238: 374-380, 1996. [PubMed: 8681948] [Full Text: https://doi.org/10.1111/j.1432-1033.1996.0374z.x]
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]