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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 breaking down glycogen into glucose in muscle cells. PHKA1 plays a critical role in cellular energy metabolism, particularly in muscles, by contributing to the regulation of glycogen breakdown.
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 encodes the alpha-1 regulatory subunit of phosphorylase b kinase, an enzyme fundamental to glycogenolysis, the process of breaking down glycogen. This enzyme is crucial for regulating energy supply, especially in muscle tissue, by converting stored glycogen into glucose when needed. Understanding PHKA1's function is important for deciphering metabolic pathways and conditions linked to impaired energy use.
What the gene does
PHKA1 is responsible for producing the alpha-1 subunit, which forms part of the phosphorylase b kinase enzyme complex. This enzyme typically comprises 16 subunits, with four copies each of alpha, beta, gamma, and delta subunits. The alpha-1 subunit, predominantly found in muscle cells, helps modulate the overall activity of the phosphorylase b kinase enzyme. This enzyme's primary role is to activate glycogen phosphorylase b, converting it to glycogen phosphorylase a. The activated form, glycogen phosphorylase a, then proceeds to break down glycogen, releasing glucose for cellular energy, a process particularly vital during physical exertion.
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Chromosome location
The PHKA1 gene is located on the long arm of the X chromosome at position Xq13.1. Its genomic position means that mutations can lead to X-linked inheritance patterns, influencing how associated conditions are passed through families.
Protein structure
The PHKA1 gene encodes a protein that is 1223 amino acids in length. This protein includes specific regions that are crucial for its function. There are two identified calmodulin-binding regions, located at amino acids 810-840 and 1046-1086, respectively. Additionally, a disordered region has been identified between amino acids 1021 and 1056, which may contribute to the protein's flexibility and interaction with other molecules.
Key variants
Genetic variants within the PHKA1 gene can alter the structure or function of the alpha-1 subunit, potentially impairing the activity of phosphorylase b kinase. These changes can lead to disruptions in glycogen metabolism, particularly in muscle tissue. The clinical impact of PHKA1 variants can range from mild symptoms to more pronounced metabolic conditions.
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.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.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 |
c.2479C>T | p.Arg827Ter | Pathogenic | ★☆☆☆ | not provided |
c.2695_2696delinsCACACAGTCATATGCATAC | p.Val899fs | Pathogenic | ★☆☆☆ | not provided |
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 PHKA1 gene are associated with forms of glycogen storage disease type IX (GSD IX), specifically GSD IXd or X-linked muscle glycogenosis. This condition primarily affects muscles, leading to symptoms such as muscle weakness, pain, and cramping, particularly during exercise. Some individuals carrying PHKA1 variants may not experience noticeable symptoms, highlighting the variability in clinical presentation.
No disease links recorded for this gene in our reference set.
UK clinical status
The PHKA1 gene is reviewed by the UK's NHS Genomic Medicine Service. It is listed as 'green' on several PanelApp panels, including those for Acute rhabdomyolysis (R419), Glycogen storage disease (R274), Likely inborn error of metabolism (R98), Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82), Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders. A 'green' rating indicates that there is strong evidence supporting a gene's association with the listed conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the PHKA1 gene?
The PHKA1 gene provides instructions for making the alpha-1 subunit of the phosphorylase b kinase enzyme, which is crucial for breaking down glycogen into glucose in muscle cells to supply energy.
What conditions are associated with variants in the PHKA1 gene?
Variants in the PHKA1 gene are associated with certain forms of glycogen storage disease type IX, specifically GSD IXd or X-linked muscle glycogenosis, which can cause muscle weakness and pain.
Is PHKA1 involved in muscle function?
Yes, the PHKA1 gene is particularly important for muscle function as its encoded protein is most abundant in muscle cells and plays a key role in providing energy for muscle activity through glycogen breakdown.
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