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PHKA1
phosphorylase kinase regulatory subunit alpha 1
The PHKA1 gene provides instructions for the alpha-1 subunit of phosphorylase b kinase, an enzyme essential for glycogen breakdown and energy production in muscle cells. PHKA1 is a gene that codes for a key regulatory component of the phosphorylase b kinase enzyme.
PHKA1 is located on the long (q) arm of chromosome X, at band Xq13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The PHKA1 gene, also known as phosphorylase kinase regulatory subunit alpha 1, is crucial for muscle function and energy metabolism. It contains the genetic blueprint for a specific subunit of the phosphorylase b kinase enzyme. This enzyme is involved in breaking down glycogen, a stored form of glucose, into usable energy, especially important during muscle activity. Disruptions in PHKA1 can impair this process, affecting muscle function.
What the gene does
The PHKA1 gene provides instructions for synthesising the alpha-1 subunit, which is one of four types of subunits making up the phosphorylase b kinase enzyme. This complex enzyme typically consists of 16 subunits in total: four alpha, four beta, four gamma, and four delta subunits. The alpha-1 subunit, specifically encoded by PHKA1, is predominantly found in muscle cells and is responsible for regulating the overall activity of the phosphorylase b kinase enzyme. Phosphorylase b kinase is instrumental in cellular energy supply by activating another enzyme called glycogen phosphorylase b. This activation leads to the breakdown of glycogen, a stored form of glucose in muscle and liver cells, into glucose, which is then used for energy, particularly during periods of high demand such as exercise.
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Chromosome location
The PHKA1 gene is situated on the X chromosome at position Xq13.1. This genomic location indicates that the gene resides on the long arm of the X chromosome. As an X-linked gene, its inheritance pattern can vary and may affect males and females differently.
Protein structure
The PHKA1 protein, comprising 1223 amino acids, contains several distinct functional regions. Among these are two identified calmodulin-binding regions. The first calmodulin-binding region spans amino acids 810 to 840, and a second calmodulin-binding region is located between amino acids 1046 and 1086. Additionally, a disordered region is identified from amino acids 1021 to 1056, which can suggest flexibility or involvement in multiple protein interactions.
Key variants
Genetic variations within the PHKA1 gene can lead to alterations in the structure or function of the alpha-1 subunit of phosphorylase b kinase. These changes may impact the enzyme's ability to effectively break down glycogen. Variants can include single nucleotide changes, insertions, or deletions, each potentially affecting protein synthesis or activity differently.
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.1039C>T | p.Gln347Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXd |
c.1174C>T | p.Arg392Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXd |
c.2587C>T | p.Arg863Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2603_2604del | p.Ser868fs | Pathogenic | ★★☆☆ | Glycogen storage disease IXd |
c.2606+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen phosphorylase kinase deficiency |
c.2716C>T | p.Arg906Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease IXd |
c.3334G>T | p.Glu1112Ter | Pathogenic | ★★☆☆ | Glycogen storage disease IXd |
c.892C>T | p.Arg298Ter | Pathogenic | ★★☆☆ | Glycogen phosphorylase kinase deficiency |
c.1571_1572dup | p.Ile525fs | Pathogenic | ★☆☆☆ | Glycogen phosphorylase kinase deficiency |
c.2091C>A | p.Cys697Ter | Pathogenic | ★☆☆☆ | Glycogen phosphorylase kinase deficiency |
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 PHKA1 gene are associated with certain inherited metabolic conditions. One such condition is a form of glycogen storage disease type IX (GSD IX), specifically known as GSD IXd or X-linked muscle glycogenosis. This rare disorder primarily affects muscles, potentially causing symptoms such as muscle weakness, pain, and cramping, especially during physical exertion, though some individuals may experience no noticeable symptoms.
No disease links recorded for this gene in our reference set.
UK clinical status
PHKA1 is included in several NHS Genomic Medicine Service national test panels, indicating its clinical relevance for various conditions. These panels include 'Acute rhabdomyolysis', 'Glycogen storage disease', 'Likely inborn error of metabolism', 'Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies', 'Rhabdomyolysis and metabolic muscle disorders', and 'Undiagnosed metabolic disorders'. This inclusion supports its role in the genetic diagnosis of these conditions within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the PHKA1 gene?
The PHKA1 gene provides instructions for making the alpha-1 subunit of the phosphorylase b kinase enzyme. This enzyme is crucial for breaking down glycogen in muscle cells to produce glucose for energy, particularly during exercise.
What health condition is associated with PHKA1 variants?
Variants in the PHKA1 gene are associated with a rare form of glycogen storage disease type IX, specifically GSD IXd or X-linked muscle glycogenosis. This condition primarily affects muscles, leading to potential weakness, pain, and cramping.
Is PHKA1 involved in muscle or liver metabolism?
The alpha-1 subunit produced from the PHKA1 gene is predominantly part of the phosphorylase b kinase enzyme found in muscle cells, indicating its primary involvement in muscle glycogen metabolism.
References
- Preisler N, Orngreen MC, Echaniz-Laguna A. Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease? Neurology. 2012. PMID: 22238410
- Ørngreen MC, Schelhaas HJ, Jeppesen TD. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology. 2008. PMID: 18401027
- Wuyts W, Reyniers E, Ceuterick C. Myopathy and phosphorylase kinase deficiency caused by a mutation in the PHKA1 gene. American journal of medical genetics. Part A. 2005. PMID: 15637709
- 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