HGNC Approved Gene Symbol: PHKA2
Cytogenetic location: Xp22.13 Genomic coordinates (GRCh38): X:18,892,298-18,984,114 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.13 | Glycogen storage disease, type IXa1 | 306000 | X-linked recessive | 3 |
| Glycogen storage disease, type IXa2 | 306000 | X-linked recessive | 3 |
The PHKA2 gene on chromosome Xp22 encodes the alpha subunit of hepatic phosphorylase kinase (PHK; EC 2.7.11.19). Hepatic phosphorylase kinase is a hexadecameric enzyme comprising 4 copies each of 4 unique subunits encoded by 4 different genes: alpha (PHKA2), beta (PHKB, 172490), gamma (PHKG2, (172471)), and delta. The delta subunit can be encoded by 3 different genes (CALM1, 114180; CALM2, 114182; or CALM3, 114183). The PHKA1 (311870) and PHKG1 (172470) genes encode the alpha and gamma subunits, respectively, of muscle phosphorylase kinase; the beta subunit is the same in both 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).
Davidson et al. (1992) isolated clones corresponding to the Phka2 gene from a rabbit cDNA library. The deduced 1,235-residue protein showed 68% sequence similarity to the rabbit Phka1 gene. The placement of nucleotide and residue differences indicated that Phka1 and Phka2 are encoded by 2 separate genes, rather than being generated by alternative splicing of a single gene. Northern blot analysis identified a 4.3-kb mRNA Phka2 transcript with high expression in liver and brain, but not in muscle.
Hendrickx et al. (1992, 1993) isolated a clone for the human PHKA2 gene from a human hepatoma cDNA library. The protein showed 93.5% homology to the rabbit protein. Two calmodulin binding sites identified in rabbit Phka1 are highly conserved in rabbit and human PHKA2. Differential splicing was observed.
Using the rabbit Phka2 gene, Davidson et al. (1992) mapped the human homolog, PHKA2, to chromosome Xp22.2-p22.1. By in situ hybridization, Wauters et al. (1992) demonstrated that the PHKA2 gene is located in the distal part of Xp in the same region as the mutation for X-linked liver glycogenosis (GSD IXa; 306000). By fluorescence in situ hybridization, Hendrickx et al. (1992, 1993) mapped the human PHKA2 gene to Xp22. It is noteworthy that PHKA1 and PHKA2 are located on Xq and Xp, respectively.
In the mouse, Ryder-Cook et al. (1989) mapped the alpha subunit of phosphorylase kinase to the X chromosome. They noted that the beta, gamma, and delta subunits are autosomal.
Hendrickx et al. (1999) determined that the human PHKA2 gene contains 33 exons and spans 65 kb or more.
In patients with X-linked hepatic glycogen storage disease (GSD9A; see 306000), Hendrickx et al. (1995) identified 4 different mutations in the PHKA2 gene (300798.0001-300798.0004).
Van den Berg et al. (1995) identified mutations in the PHKA2 gene (300798.0005 and 300798.0006) in affected members of 2 Dutch families with GSD IXa1. One of the families had been reported by Huijing and Fernandes (1969).
Burwinkel et al. (1996) identified mutations in the PHKA2 gene in patients with GSD IXa2 (306000.0007-306000.0010). The mutations appeared to cluster in limited sequence regions. Burwinkel et al. (1996) stressed that the clustering of GSD IXa2 mutations would further facilitate analysis by RT-PCR of blood cell mRNA and thus help avoid liver biopsy in the diagnosis.
In a Japanese boy with classic GSD IXa2, Fukao et al. (2007) identified a hemizygous 10-kb deletion in the PHKA2 gene, resulting in the deletion of exons 20 to 26. Studies of the breakpoint regions showed that the deletion resulted from Alu element-mediated unequal homologous recombination.
Roscher et al. (2014) reported 7 novel mutations in the PHKA2 gene resulting in GSD IXa.
In 4 unrelated patients with GSD IXa2, Hendrickx et al. (1996) identified 4 different mutations in the PHKA2 gene (306000.0011-306000.0014). The mutations resulted in minor abnormalities in the primary structure of the protein. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that may be involved in the regulation of PHK. Hendrickx et al. (1996) postulated that PHK activity may be regulated by phosphorylation of these sites and that type II GSD9A may be due to impaired activation of PHK activity. The findings may explain why the in vitro PHK enzymatic activity is not deficient in type II, whereas it is in type I.
Hendrickx et al. (1999) identified PHKA2 mutations in 10 patients with GSD9A, types I and II. They proposed that mutations in GSD type I, in which PHK activity is decreased in both liver and erythrocytes, results from truncation or disruption of the PHKA2 protein. In contrast, all type II mutations, which result in residual activity in erythrocytes, were missense mutations or small in-frame deletions and insertions. These results suggested that the biochemical differences between the 2 types of GSD IXa are due to the different nature of the disease-causing mutations in PHKA2. Type I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas type II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.
In a Belgian boy with glycogen storage disease IXa1 (GSD9A1; 306000), Hendrickx et al. (1995) identified a C-to-T transition in exon 8, resulting in a gln1009-to-ter (Q1009X) substitution. This led to a truncated protein that lacked the C terminus, the phosphorylation site, and a putative calmodulin-binding site. The patient had hepatomegaly, elevated liver enzymes, and growth retardation that decreased with puberty. PHK activity was completely absent from erythrocytes and liver.
In a French boy with GSD type IXa1 (GSD9A1; 306000), Hendrickx et al. (1995) found a C-to-T transition in exon 2 of the PHKA gene, resulting in a gln766-to-ter (Q766X) substitution. This led to a truncated protein that lacked the C terminus, the phosphorylation site, and both putative calmodulin-binding sites. The patient had hepatomegaly, elevated liver enzymes, and growth retardation. Erythrocyte PHK activity was 2% of control values. His mildly affected sister had only hepatomegaly; her erythrocyte PHK activity was 30% of control values.
In twin boys from the U.K. with GSD type IXa1 (GSD9A1; 306000), Hendrickx et al. (1995) found a G-to-T transversion at position +1 of intron 7 of the PHKA2 gene. This resulted in complete skipping of exon 7 and a PHKA2 protein lacking the 34 amino acids of this exon. Both patients had hepatomegaly, growth retardation, and hypertriglyceridemia, but not hypercholesterolemia. Only 1 had increased liver enzymes. Hepatomegaly disappeared in both boys between ages 8 and 10 years. Erythrocyte activity was 8 and 4% of control values, respectively.
In 2 brothers from the U.K. with GSD type IXa1 (GSD9A1; 306000), Hendrickx et al. (1995) found a C-to-A transversion in exon 11 of the PHKA2 gene, resulting in a ser1049-to-ter (S1049X) substitution and protein lacking more than 180 amino acids of the C terminus, including the 3-prime putative calmodulin binding site. Both patients had growth retardation, hepatomegaly, and elevated liver enzymes. Erythrocyte PHK activity was 5.7 and 16.9% of control values, respectively.
In affected members of a large Dutch family with GSD type IXa1 (GSD9A1; 306000) previously described by Huijing and Fernandes (1969) and Willems et al. (1990), van den Berg et al. (1995) found a 3614C-T transition in the PHKA2 gene, resulting in a pro1205-to-leu (P1205L) substitution in a highly conserved region of the protein.
In a Dutch boy with GSD type IXa1 (GSD9A1; 306000), van den Berg et al. (1995) found a 3-bp deletion (419_421), resulting in deletion of phenylalanine-141 from the gene product. The same deletion was found in the PHKA2 coding sequence from lymphocytes of the patient's mother in heterozygous state. This phenylalanine is a highly conserved amino acid between species.
Burwinkel et al. (1996) identified an A-to-G transition in the PHKA2 gene, resulting in an asp299-to-gly (D299G) substitution, in a patient they classified as having X-linked GSD IXa2 (GSD9A2; see 306000). However, Beauchamp et al. (2007) identified the D299G mutation in a patient with reduced PHK activity in erythrocytes and leukocytes, consistent with GSD IXa1 (306000). They suggested that D299G should be reclassified as a GSD IXa1 mutation.
In a patient with X-linked GSD IXa2 (GSD9A2; see 306000), Burwinkel et al. (1996) identified a G-to-A transition in the PHKA2 gene, resulting in an arg186-to-his (R186H) substitution.
Hendrickx et al. (1998) presented clinical, biochemical, and molecular findings in a patient with type II X-linked liver glycogenosis and the R186H mutation in the PHKA2 gene. The patient had been followed for 40 years. Although growth was retarded early in life, he achieved a height of 182 cm at the age of 33 years. Thyroid therapy appeared to be helpful in this patient. Five male relatives also had liver glycogenosis.
In a patient with GSD IXa2 (GSD9A2; 306000), Burwinkel et al. (1996) identified an A-to-C transversion in the PHKA2 gene, resulting in a his132-to-pro (H132P) substitution.
In a patient with GSD IXa2 (GSD9A2; see 306000), Burwinkel et al. (1996) identified a C-to-T change in the PHKA2 gene, resulting in a his132-to-tyr (H132Y) substitution.
In a patient with X-linked GSD IXa2 (GSD9A2; see 306000), Hendrickx et al. (1996) identified a 3341C-T change in the PHKA2 gene, resulting in a thr1114-to-ile (T1114I) substitution.
In a patient with X-linked GSD type IXa2 (GSD9A2; see 306000), Hendrickx et al. (1996) identified a 556C-T transition in the PHKA2 gene, resulting in an arg556-to-cys (R556C) substitution.
In a patient with X-linked GSD IXa2 (see GSD9A2; see 306000), Hendrickx et al. (1996) identified an in-frame 3-bp deletion (750_752) in the PHKA2 gene, resulting in the deletion of thr251.
In a patient with X-linked GSD type IXa2 (GSD9A2; see 306000), Hendrickx et al. (1996) identified an in-frame 6-bp insertion between nucleotides 3331 and 3332 of the PHKA2 gene, resulting in the insertion of a threonine and an arginine residue between arg1111 and glu1112 (R1111insTR).
In a patient with X-linked GSD IXa2 (GSD9A2; see 306000), Burwinkel et al. (1998) described an A-to-G transition in the PHKA2 coding sequence, resulting in a lys189-to-glu (K189E) substitution. The phenotype in the patient was that of low PHK activity in liver tissue, but activity in erythrocytes was 4-fold higher than normal.
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