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PRKAR1A
protein kinase cAMP-dependent type I regulatory subunit alpha
The PRKAR1A gene provides instructions for a regulatory subunit of protein kinase A (PKA), an enzyme essential for controlling cell growth and division within the body. PRKAR1A encodes a key component of protein kinase A, an enzyme that acts as a master regulator of numerous cellular processes, including metabolism, growth, and immune response.
PRKAR1A is located on the long (q) arm of chromosome 17, at band 17q24.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 17 in the library →Overview
The PRKAR1A gene, or protein kinase cAMP-dependent type I regulatory subunit alpha, is crucial for normal cellular function. It provides the genetic blueprint for one of the regulatory subunits of protein kinase A (PKA), a central enzyme involved in regulating cell growth, division, and metabolism. PKA activity is tightly controlled, and the PRKAR1A-encoded subunit is vital for this regulation, ensuring the enzyme is activated only when necessary.
Disruptions to the PRKAR1A gene can lead to uncontrolled PKA activity, which is implicated in the development of various medical conditions. Understanding the PRKAR1A gene's function and its role in PKA regulation is therefore important for comprehending the mechanisms underlying these conditions.
What the gene does
The PRKAR1A gene is responsible for producing the regulatory subunit type I alpha of protein kinase A (PKA). PKA is a tetrameric enzyme, meaning it is composed of four protein subunits: two regulatory subunits and two catalytic subunits. The regulatory subunits, including the one encoded by PRKAR1A, bind to the catalytic subunits and inhibit their activity when PKA is inactive. This mechanism prevents PKA from constantly phosphorylating its target proteins.
When cyclic adenosine monophosphate (cAMP), a crucial secondary messenger molecule, levels rise within the cell, cAMP binds to the regulatory subunits of PKA. This binding causes a conformational change in the regulatory subunits, leading them to dissociate from the catalytic subunits. Once freed, the catalytic subunits become active and can then phosphorylate specific serine and threonine residues on various target proteins. This phosphorylation event can alter the activity, localisation, or stability of these proteins, thereby influencing a wide array of cellular processes.
Key cellular functions regulated by PKA and, by extension, by the PRKAR1A gene product, include gene transcription, glycogenolysis (the breakdown of glycogen into glucose), lipolysis (the breakdown of fats), and cell proliferation. Pathogenic variants in PRKAR1A often result in a reduction of functional regulatory subunits. This decrease in regulatory control leads to constitutive, or always-on, activation of PKA, even in the absence of elevated cAMP. Such chronic activation can disrupt normal cell signalling pathways, promoting abnormal cell growth and division, which underlies the development of conditions associated with PRKAR1A variants.
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Chromosome location
The PRKAR1A gene is situated on chromosome 17 at band 17q24.2. This specific location on the long arm (q) of chromosome 17 provides the genomic address for the gene, helping to map its position within the human genome. The gene spans a region of DNA that contains the instructions for synthesising the PRKAR1A protein.
Protein structure
The PRKAR1A protein is 381 amino acids in length and comprises several functional regions crucial for its role as a regulatory subunit of protein kinase A. The Dimerization and phosphorylation region, spanning amino acids 1-136, is integral for the protein to form dimers, which are necessary for its inhibitory function on the catalytic subunits of PKA. This region also contains sites that can be phosphorylated, adding another layer of regulatory control.
Within this larger region, a specific Disordered region from amino acids 64-96 indicates a segment of the protein that lacks a fixed three-dimensional structure under physiological conditions. Such regions are often involved in molecular recognition and binding to multiple partners. Furthermore, a Pseudophosphorylation motif is located at amino acids 96-100. This motif may mimic the presence of a phosphate group, potentially influencing protein interactions or activity, even if it is not actually phosphorylated.
Key variants
Variants in the PRKAR1A gene can significantly impact its function, often leading to altered protein kinase A (PKA) activity. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their effect depends on the specific change and its location within the gene. Many pathogenic variants result in a reduced amount of functional PRKAR1A protein or produce a protein that cannot properly bind to PKA's catalytic subunits or cAMP. This typically leads to a loss of regulatory control, resulting in persistently active PKA.
The clinical consequences of PRKAR1A variants are diverse, influencing various bodily systems due to PKA's broad role in cell signalling. Identifying specific variants is an important step in understanding the genetic basis of associated 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.1102C>T | p.Arg368Ter | Pathogenic | ★★☆☆ | Acrodysostosis 1 with or without hormone resistance |
c.124C>T | p.Arg42Ter | Pathogenic | ★★☆☆ | Carney complex, type 1 |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Carney complex, type 1 |
c.221_230del | p.Arg74fs | Pathogenic | ★★☆☆ | Carney complex, type 1 |
c.289C>T | p.Arg97Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.46C>T | p.Arg16Ter | Pathogenic | ★★☆☆ | not provided |
c.491_492del | p.Val164fs | Pathogenic | ★★☆☆ | Carney complex, type 1 |
c.502+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Carney complex, type 1 |
c.535C>T | p.Gln179Ter | Pathogenic | ★★☆☆ | not provided |
c.549+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Carney complex, type 1 |
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 PRKAR1A gene are primarily associated with inherited conditions that manifest with a range of symptoms, often affecting multiple organ systems. The most well-known condition linked to PRKAR1A is Carney complex, an autosomal dominant disorder characterised by various skin pigmentations and an increased risk of developing benign and malignant tumours in several endocrine glands and other tissues. Another condition, Carney complex type 1, is specifically attributed to PRKAR1A variants.
These conditions typically arise from the disruption of protein kinase A (PKA) regulation due to the altered function of the PRKAR1A protein, leading to uncontrolled cell growth and division.
- Carney complex type 1
- Carney complex Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic PRKAR1A variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The PRKAR1A gene is recognised within the UK's National Health Service (NHS) Genomic Medicine Service, indicating its clinical relevance for diagnostic testing. It is listed as 'green' on several NHS Genomic Medicine Service 'PanelApp' panels, signifying that there is sufficient evidence for genes on these panels to be routinely sequenced in a clinical diagnostic setting for specific conditions. This includes panels for Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis, Carney complex, Childhood solid tumours, Congenital hypothyroidism, DDG2P, Endocrine neoplasia, Foetal anomalies, Inherited non-medullary thyroid cancer, Inherited phaeochromocytoma and paraganglioma, Multiple endocrine tumours, Pigmentary skin disorders, Primary pigmented nodular adrenocortical disease, Skeletal dysplasia, and Thyroid cancer pertinent cancer susceptibility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
While specific lifestyle interventions cannot alter the genetic basis of PRKAR1A-related conditions, general health-promoting behaviours are broadly recommended. Maintaining a balanced diet rich in fruits, vegetables, and whole grains is important for overall well-being. Regular physical activity, in accordance with national guidelines, can help support cardiovascular health and maintain a healthy weight. Managing stress through techniques like mindfulness or exercise may also contribute to general health.
Research suggests that some environmental factors can influence the manifestation of certain genetic predispositions, though direct evidence for PRKAR1A-related conditions is still emerging. For individuals with a PRKAR1A variant, it is particularly important to engage in regular medical surveillance as recommended by their healthcare provider, given the increased risk of developing various tumours. Avoiding smoking and excessive alcohol consumption are also general recommendations for reducing cancer risk in the general population.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions caused by PRKAR1A variants. Any claims regarding supplements for genetic conditions should be approached with caution, as many lack robust clinical backing. While certain vitamins or minerals are essential for general health, taking them in excess or without medical advice is not recommended.
Individuals considering any dietary supplements should always discuss this with their healthcare provider. A healthcare professional can assess individual needs, evaluate potential interactions with medications, and provide guidance based on the latest evidence-based information, ensuring safety and efficacy.
Frequently asked questions
What is the primary function of the PRKAR1A gene?
The PRKAR1A gene provides instructions for making a regulatory subunit of protein kinase A (PKA), an enzyme critical for controlling cell growth, division, and metabolism. It helps ensure PKA is only active when needed.
What happens if there is a variant in the PRKAR1A gene?
Variants in PRKAR1A can lead to a reduction in functional regulatory subunits, causing protein kinase A to be overactive. This uncontrolled PKA activity can disrupt normal cell signalling, potentially leading to abnormal cell growth and various health conditions.
What conditions are associated with PRKAR1A gene variants?
The PRKAR1A gene is primarily associated with Carney complex and Carney complex type 1, which are inherited disorders characterised by skin pigmentation changes and an increased risk of developing various benign and malignant tumours.
Is Carney complex inherited?
Yes, Carney complex is typically inherited in an autosomal dominant pattern. This means that only one copy of the altered PRKAR1A gene in each cell is sufficient to cause the condition.
Where is the PRKAR1A gene located?
The PRKAR1A gene is located on chromosome 17 at position 17q24.2. This specifies its precise address within the human genome.
Can lifestyle changes help manage PRKAR1A-related conditions?
While lifestyle changes cannot alter the underlying genetic cause, maintaining a healthy lifestyle through a balanced diet, regular exercise, and avoiding smoking can support overall health and may help manage general health risks. Regular medical surveillance, as advised by a healthcare provider, is crucial for individuals with PRKAR1A variants.
References
- Pereira AM, Hes FJ, Horvath A. Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. The Journal of clinical endocrinology and metabolism. 2010. PMID: 19915019
- Bertherat J, Horvath A, Groussin L. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. The Journal of clinical endocrinology and metabolism. 2009. PMID: 19293268
- Kirschner LS. Use of mouse models to understand the molecular basis of tissue-specific tumorigenesis in the Carney complex. Journal of internal medicine. 2009. PMID: 19522826
- Horvath A, Bossis I, Giatzakis C. Large deletions of the PRKAR1A gene in Carney complex. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008. PMID: 18223213
- Kirschner LS, Carney JA, Pack SD. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nature genetics. 2000. PMID: 10973256
- Adam MP, Bick S, Mirzaa GM. Carney Complex. 1993. PMID: 20301463