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PHKG2
phosphorylase kinase catalytic subunit gamma 2
The PHKG2 gene provides instructions for a crucial component of an enzyme called phosphorylase kinase, which plays a vital role in the breakdown of glycogen for energy. PHKG2 encodes the gamma-2 subunit of phosphorylase kinase, an enzyme primarily active in the liver.
PHKG2 is located on the short (p) arm of chromosome 16, at band 16p11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The PHKG2 gene provides the genetic blueprint for the gamma-2 subunit of the phosphorylase kinase enzyme. This enzyme is critical for carbohydrate metabolism, specifically the process of glycogenolysis, which is the breakdown of glycogen into glucose. Glycogen serves as the body's primary stored form of glucose, providing energy to cells and maintaining stable blood sugar levels.
What the gene does
The phosphorylase kinase enzyme is a complex structure composed of 16 subunits, with four copies each of alpha, beta, gamma, and delta subunits. The gamma subunit, produced from the PHKG2 gene, is the catalytic component responsible for the enzyme's function. While the other subunits help regulate its activity, the gamma-2 subunit is particularly abundant in the liver, where it plays a key role in activating glycogen phosphorylase b. This activation leads to the breakdown of glycogen into glucose, which can then be released into the bloodstream to meet the body's energy demands or to prevent hypoglycaemia (low blood sugar).
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Chromosome location
The PHKG2 gene is situated on chromosome 16 at position 16p11.2. This location refers to the short arm of chromosome 16, within band 11.2.
Protein structure
The PHKG2 protein consists of 406 amino acids. It features a prominent Protein kinase domain spanning amino acids 24-291, which is responsible for its enzymatic activity. Additionally, the protein contains two Calmodulin-binding regions: one at the N-terminus from amino acids 306-330, and another at the C-terminus from amino acids 346-370. These calmodulin-binding domains are important for regulatory interactions.
Key variants
Genetic variations within the PHKG2 gene can alter the protein's structure and function, potentially affecting its ability to properly regulate glycogen breakdown. These variations include various types of changes to the DNA sequence, such as substitutions, deletions, or insertions, which may lead to impaired enzyme activity.
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.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 type 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 phosphorylase kinase deficiency |
c.96-11G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | PHKG2-related disorder |
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
Pathogenic variants in the PHKG2 gene are primarily associated with Glycogen storage disease type IX, specifically a form known as GSD IXc. This condition predominantly affects the liver, leading to symptoms such as an enlarged liver (hepatomegaly), slowed growth, and episodes of low blood glucose (hypoglycaemia). While these symptoms often improve with age, the underlying genetic cause remains.
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 clinical panels in the UK. These include panels for Glycogen storage disease (R274), Ketotic hypoglycaemia, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders, indicating its recognised role in these conditions within a clinical setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Glycogen Storage Disease Type IX?
Glycogen Storage Disease Type IX (GSD IX) is a group of inherited disorders affecting the body's ability to break down glycogen. GSD IXc, specifically linked to PHKG2, primarily impacts the liver's function in releasing stored glucose.
How does the PHKG2 gene affect blood sugar levels?
The PHKG2 gene product, the gamma-2 subunit of phosphorylase kinase, activates an enzyme crucial for breaking down glycogen into glucose. When this process is impaired due to PHKG2 variants, the body may struggle to maintain normal blood glucose levels, potentially leading to hypoglycaemia.
Is Glycogen Storage Disease Type IX a lifelong condition?
For GSD IXc caused by PHKG2 variants, symptoms such as an enlarged liver and low blood glucose often improve over time. However, the genetic predisposition remains, and ongoing management may be necessary.
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