On this page
PHKG2
phosphorylase kinase catalytic subunit gamma 2
The PHKG2 gene provides instructions for a key component of an enzyme called phosphorylase b kinase, which is vital for breaking down glycogen in the liver to release glucose. PHKG2 encodes the gamma-2 catalytic subunit of liver phosphorylase b kinase.
PHKG2 is located on the short (p) arm of chromosome 16, at band 16p11.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 16 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The PHKG2 gene, or phosphorylase kinase catalytic subunit gamma 2, contains the genetic blueprint for a crucial component of the phosphorylase b kinase enzyme. This enzyme is particularly important in the liver, where it regulates the release of glucose from glycogen stores. Maintaining appropriate glucose levels is essential for overall bodily function and energy supply.
Changes within the PHKG2 gene can disrupt this process, potentially leading to inherited metabolic disorders, specifically certain forms of glycogen storage disease.
What the gene does
The PHKG2 gene directs the synthesis of the gamma-2 subunit, which is the catalytic component of the phosphorylase b kinase enzyme. This enzyme is a complex structure typically comprising 16 subunits, with four copies each of alpha, beta, gamma, and delta subunits. While the gamma-2 subunit carries out the primary enzymatic function, the other subunits are involved in regulating its activity.
Phosphorylase b kinase plays a central role in glycogenolysis, the process by which stored glycogen is broken down into glucose. It activates another enzyme, glycogen phosphorylase b, converting it into its active form, glycogen phosphorylase a. This cascade ensures that glucose can be rapidly mobilised from liver glycogen reserves, particularly to maintain blood glucose levels between meals or during periods of increased energy demand.
Video: Genetics 101
Chromosome location
The PHKG2 gene is situated on chromosome 16 at position 16p11.2. This specific genomic location provides the cellular machinery with the precise instructions for manufacturing the gamma-2 subunit of phosphorylase b kinase.
Protein structure
The protein encoded by the PHKG2 gene is 406 amino acids in length. It features a prominent Protein kinase domain spanning amino acids 24 to 291, which is responsible for its catalytic activity. Additionally, the protein contains two distinct Calmodulin-binding regions: one at the N-terminus (amino acids 306-330) and another at the C-terminus (amino acids 346-370), which are important for regulatory interactions.
Key variants
Genetic variations within the PHKG2 gene can lead to alterations in the structure or function of the phosphorylase b kinase gamma-2 subunit. These changes, known as variants, can impact the enzyme's ability to effectively break down glycogen and manage glucose levels in the body. Identifying specific variants helps in understanding their potential clinical significance.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.226C>T | p.Arg76Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHKG2-related disorder |
c.22G>T | p.Glu8Ter | Pathogenic | ★★☆☆ | Glycogen storage disease IXc |
c.334_337del | p.Lys112fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXc |
c.431T>C | p.Leu144Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXc |
c.454C>T | p.Arg152Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXc |
c.469G>A | p.Glu157Lys | Pathogenic | ★★☆☆ | Glycogen storage disease IXc |
c.553C>T | p.Arg185Ter | Pathogenic | ★★☆☆ | Glycogen storage disease type IXc |
c.643G>A | p.Asp215Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen phosphorylase kinase deficiency |
c.800_801+34del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXc |
c.835C>T | p.Arg279Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXc |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the PHKG2 gene are known to cause Glycogen storage disease type IXc (GSD IXc). This condition primarily affects the liver, leading to symptoms such as an enlarged liver (hepatomegaly), slower-than-average growth, and episodes of low blood glucose (hypoglycaemia). While these symptoms often improve with age, understanding the genetic basis is crucial for management.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PHKG2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The PHKG2 gene is included on several NHS Genomic Medicine Service panels, indicating its recognised clinical significance within the UK healthcare system. It is listed on panels for Glycogen storage disease, Ketotic hypoglycaemia, Likely inborn error of metabolism, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the PHKG2 gene?
The PHKG2 gene provides instructions for the gamma-2 subunit of phosphorylase b kinase, an enzyme crucial for breaking down stored glycogen in the liver to release glucose and maintain blood sugar levels.
What condition is associated with PHKG2 gene variants?
Pathogenic variants in the PHKG2 gene are associated with Glycogen Storage Disease Type IXc, which primarily affects liver function and glucose metabolism.
How does the PHKG2 protein contribute to glycogen breakdown?
The PHKG2 protein, as the catalytic part of phosphorylase b kinase, activates another enzyme called glycogen phosphorylase b. This activation initiates the breakdown of glycogen into glucose within the liver.
References
- Bali DS, Goldstein JL, Fredrickson K. Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene. Molecular genetics and metabolism. 2014. PMID: 24389071
- Burwinkel B, Rootwelt T, Kvittingen EA. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatric research. 2003. PMID: 12930917
- Brushia RJ, Walsh DA. Phosphorylase kinase: the complexity of its regulation is reflected in the complexity of its structure. Frontiers in bioscience : a journal and virtual library. 1999. PMID: 10487978
- Burwinkel B, Shiomi S, Al Zaben A. Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. Human molecular genetics. 1998. PMID: 9384616
- Maichele AJ, Burwinkel B, Maire I. 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 genetics. 1996. PMID: 8896567