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PHKB
phosphorylase kinase regulatory subunit beta
The PHKB gene provides instructions for a regulatory subunit of phosphorylase b kinase, an enzyme crucial for breaking down glycogen to supply energy to cells. The PHKB gene is responsible for producing the beta subunit of 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 phosphorylase b kinase, a complex enzyme involved in glycogenolysis, the process of breaking down glycogen. Glycogen serves as the primary stored form of glucose in the body, predominantly in muscle and liver cells. The enzyme's function is critical for maintaining cellular energy supply, especially during periods of high demand like physical exercise.
The beta subunit, produced from the PHKB gene, helps regulate the overall activity of the phosphorylase b kinase enzyme. Disruptions to this gene's function can therefore impair the body's ability to properly manage glucose levels and energy production.
What the gene does
The PHKB gene provides the blueprint for the beta subunit, a key regulatory component of the phosphorylase b kinase enzyme. This enzyme is composed of 16 subunits, with four copies each of alpha, beta, gamma, and delta subunits, each derived from a different gene. The beta subunit specifically helps to modulate the enzyme's activity.
Phosphorylase b kinase is abundant in the liver and muscles, and plays a crucial role in cellular energy metabolism. Its primary function is to activate another enzyme, glycogen phosphorylase b, by converting it into its more active form, glycogen phosphorylase a. Active glycogen phosphorylase a then facilitates the breakdown of glycogen, releasing glucose for energy. This process is essential for providing readily available energy, particularly when glucose is needed quickly, such as during physical activity.
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Chromosome location
The PHKB gene is located on chromosome 16, specifically at position 16q12.1. This genomic address indicates its precise position on the long arm ('q') of chromosome 16.
Protein structure
The PHKB protein consists of 1093 amino acids. It features several calmodulin-binding regions, which are found at amino acid positions 7-29, 768-795, and 920-951. Additionally, a disordered region is present between amino acids 689-716. These regions are important for the protein's interaction with calmodulin, a calcium-binding protein that plays a role in various cellular processes, and for maintaining its structural flexibility.
Key variants
Genetic changes, known as variants, in the PHKB gene can alter the structure or function of the beta subunit of phosphorylase b kinase. These variants can interfere with the enzyme's ability to regulate glycogen breakdown, leading to an accumulation of glycogen in affected tissues. The impact of a variant depends on its specific nature and location within the gene.
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 | ★★☆☆ | PHKB-related disorder |
c.1285C>T | p.Arg429Ter | Pathogenic | ★★☆☆ | PHKB-related disorder |
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 phosphorylase kinase deficiency |
c.2623C>T | p.Arg875Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen phosphorylase kinase deficiency |
c.2830C>T | p.Arg944Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PHKB-related disorder |
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 |
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 associated with inherited conditions primarily affecting glycogen metabolism. These conditions typically result from the impaired function of the phosphorylase b kinase enzyme, leading to an inability to properly break down stored glycogen. One such condition is glycogen storage disease type IX, which can affect both the liver and muscles.
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 NHS England Genomic Medicine Service national test panels. It is listed with a 'green' status for Glycogen storage disease (R274), Ketotic hypoglycaemia, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders, indicating that it is routinely analysed in the UK for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the PHKB gene in the body?
The PHKB gene provides instructions for the beta subunit of the phosphorylase b kinase enzyme. This enzyme is essential for breaking down glycogen, the stored form of glucose, into glucose for energy, particularly in the liver and muscles.
How does PHKB relate to glycogen storage diseases?
Variants in the PHKB gene can lead to reduced function of the phosphorylase b kinase enzyme. This impairment prevents the efficient breakdown of glycogen, causing it to accumulate in tissues and contributing to conditions such as glycogen storage disease type IX.
What tissues are primarily affected by PHKB gene variations?
Variations in the PHKB gene primarily affect tissues where glycogen is stored and metabolised, namely the liver and muscles. This can lead to symptoms related to energy deficiency and organ dysfunction in these areas.
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