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PHKB
phosphorylase kinase regulatory subunit beta
The PHKB gene provides instructions for the beta subunit of phosphorylase b kinase, an enzyme crucial for breaking down glycogen into glucose for cellular energy. PHKB plays a vital role in energy metabolism by contributing to the phosphorylase b kinase enzyme.
PHKB is located on the long (q) arm of chromosome 16, at band 16q12.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The PHKB gene encodes the beta subunit of the phosphorylase b kinase enzyme. This enzyme is integral to regulating the breakdown of stored glycogen into glucose, a process known as glycogenolysis. Glucose serves as the primary energy source for cells, particularly during periods of high demand such as exercise.
Dysregulation of glycogen breakdown due to PHKB variants can affect energy supply to cells, primarily in the liver and muscles. Understanding the function of the PHKB gene is important for comprehending conditions related to impaired glycogen metabolism.
What the gene does
The PHKB gene provides the genetic blueprint for the beta subunit, which is a regulatory component of the phosphorylase b kinase enzyme. This complex enzyme typically consists of 16 subunits, with four copies each of alpha, beta, gamma, and delta subunits. Each of these subunits is produced from a distinct gene. The beta subunit's primary role is to modulate the overall activity of the phosphorylase b kinase.
Phosphorylase b kinase itself acts as a crucial activator for another enzyme, glycogen phosphorylase b. By converting glycogen phosphorylase b into its more active form, glycogen phosphorylase a, it initiates the breakdown of glycogen. This process is vital for releasing glucose from storage reserves in the liver and muscles, providing readily available energy for various cellular functions. The beta subunit encoded by PHKB is present in phosphorylase b kinase found in both liver and muscle tissues.
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Chromosome location
The PHKB gene is situated on chromosome 16 at position 12.1 on the long arm, denoted as 16q12.1. This specific genomic location places PHKB within a region of the chromosome where various other genes are also found. The precise mapping of PHKB to this locus helps in understanding its genetic context and potential interactions with neighbouring genetic material.
Protein structure
The PHKB gene encodes a protein composed of 1093 amino acids. This protein contains several distinct functional regions. There are three identified calmodulin-binding regions: one located near the N-terminus spanning amino acids 7-29, another at amino acids 768-795, and a third towards the C-terminus from amino acids 920-951. Additionally, a disordered region is identified between amino acids 689-716. These regions contribute to the protein's regulatory functions and its ability to interact with other molecules.
Key variants
Genetic variations within the PHKB gene can alter the structure or function of the encoded beta subunit. These changes may impact the regulatory capacity of phosphorylase b kinase, thereby affecting glycogen metabolism. Variants are classified based on their predicted impact, ranging from benign to pathogenic, with pathogenic variants being those associated with disease development.
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.1127-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen phosphorylase kinase deficiency |
c.1285C>T | p.Arg429Ter | Pathogenic | ★★☆☆ | Glycogen storage disease IXb |
c.1972-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXb |
c.2304_2305del | p.Arg768fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXb |
c.2427+965A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXb |
c.2623C>T | p.Arg875Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen phosphorylase kinase deficiency |
c.2839C>T | p.Gln947Ter | Pathogenic | ★★☆☆ | Glycogen storage disease IXb |
c.2896-1G>T | - | Pathogenic | ★★☆☆ | PHKB-related disorder |
c.570_576delinsAC | p.Gln191fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXb |
c.573_577del | p.Gln191fs | Pathogenic | ★★☆☆ | Glycogen storage disease IXb |
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 PHKB gene are known to cause a form of glycogen storage disease type IX called GSD IXb. This condition primarily affects the liver and muscles. Multiple variants in the PHKB gene have been identified as causes of GSD IXb. The clinical presentation typically includes hepatomegaly (enlarged liver) and slowed growth during childhood. Episodes of low blood glucose (hypoglycaemia) may also occur in affected individuals, particularly during fasting periods or illness.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PHKB 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 PHKB gene is included in several panels within the UK National Health Service (NHS) Genomic Medicine Service. It is recognised as having a 'green' status on PanelApp for conditions such as Glycogen storage disease (R274), Ketotic hypoglycaemia, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders, indicating its clinical relevance for these indications.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PHKB gene?
The PHKB gene provides instructions for making the beta subunit of the phosphorylase b kinase enzyme. This enzyme is crucial for breaking down glycogen, a stored form of glucose, into usable glucose for energy in cells, especially in the liver and muscles.
What condition is associated with variants in the PHKB gene?
Variants in the PHKB gene are associated with glycogen storage disease type IX, specifically type IXb. This condition primarily affects the liver and muscles, leading to issues such as an enlarged liver and slow growth.
How does PHKB contribute to energy production?
The PHKB gene's product, the beta subunit, helps regulate phosphorylase b kinase. This kinase then activates another enzyme, glycogen phosphorylase, which directly breaks down glycogen into glucose. This glucose is then used by cells as an energy source.
References
- 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, Maichele AJ, Aagenaes O. Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB). Human molecular genetics. 1997. PMID: 9215682
- van den Berg IE, van Beurden EA, de Klerk JB. Autosomal recessive phosphorylase kinase deficiency in liver, caused by mutations in the gene encoding the beta subunit (PHKB). American journal of human genetics. 1997. PMID: 9326319