PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1))

2004-10-01   Constantine A Stratakis , Ludmila Matyakhina 

Unit on Genetics &Endocrinology (UGEN), DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, MD 20892-1862, USA




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The RI alpha gene is composed of 10 coding exons of varying lengths, separated by introns, giving the gene a total length of at least 21 kb.


By alternative splicing, the PRKAR1A gene encodes 3 types of transcripts that all translate in the same protein.


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48 kDa ; contains two tandem cAMP-binding domains at the C-terminus and the dimerization domain at the N-terminus that serves also as a docking site for A Kinase Anchoring Proteins (AKAPs).
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Ubiquitously expressed, in particular in brain, endocrine tissues, adipose tissue and bone.


Predominantly cytoplasmic; nuclear traslocation possible.


Two regulatory subunits bind to two catalytic subunits forming an heterotetramer, the inactive holoenzyme protein kinase A (PKA) or cyclic AMP-dependent protein kinase. PKA activation occurs when 2 cAMP molecules bind to each regulatory subunit, eliciting a reversible conformational change that releases the now active catalytic subunits. Four different regulatory subunits and three catalytic subunits of PKA have been identified in humans. The protein encoded by PRKAR1A is just one of the four possible regulatory subunits of the PKA tetramer; however, PRKAR1A is the most abundant and widely expressed PKA subunit. Although its other functions are not fully elucidated yet, PRKAR1A may act as a tumor-suppressor gene in Carney complex (CNC) and in sporadic (non-CNC-related) adrenal and thyroid tumors.


Prkar1a, Mus musculus
Gene conserved in Mammalia: M.musculus-81.36%; R.norvegicus-97.38%; C.elegans-57.91%; D.melanogaster-72.07%; S. cerevisiae-37.41%



Most mutations are null alleles; they are dispersed throughout the coding region of the gene.


Many of tumors that develop in patients with Carney complex and PPNAD (see below) show loss of heterozygosity; somatic mutations in the PRKARIA gene have been reported in three cases of sporadic adrenocortical tumors.

Implicated in

Entity name
Carney complex syndrome, type I
A multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and some other tumors.
According to the severity of the disease in a given patient, and to the quality of a regular follow up; life span is decreased in patients with CNC. 57% of the deaths are due to heart related causes; others due to the postoperative complications or evolution of the malignant process; presymptomatic diagnosis improves survival data and might prevent earlier the main causes of death in this disease.
Limited data; some of myxomas and PPNAD from CNC patients showed telomeric associations, dicentric chromosomes, aneuploidy, polyploidy and chromosomal rearrangements.
Hybrid gene
Half of CNC patients show PRKARIA mutations.
PRKARIA is frequently affected by bi-allelic inactivation in tumors of CNC patients. However 1 kindred was described where a splice site mutation led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear level. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis in tissues in patients with CNC.
Entity name
PPNAD - Primary pigmented nodular adrenocortical disease Primary pigmented nodular adrenocortical disease
PPNAD is a cause of ACTH-independent Cushings syndrome. This condition can be difficult to diagnose because hypercortisolism may be periodic and adrenal imaging may not demonstrate an adrenal tumor.
Hybrid gene
Inactivating PRKAR1A germline mutations are frequent in sporadic and isolated cases of PPNAD.
Both alleles are frequently inactivated. The wild-type allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene.
Entity name
Adrenocortical tumors, sporadic
Patients frequently present with ACTH-independent Cushings syndrome.
Hybrid gene
Somatic mutations in the PRKAR1A gene were identified in 3 cases of sporadic adrenocortical tumor. All 3 mutations predicted premature termination of the protein. 17q23-24 loss-of-heterozygosity is a frequent event in adrenal carcinomas.
Haploinsufficiency of PRKARIA and a reversal of the ratio of R1A to R2B have been proposed to cause tumorigenesis, at least in some cases.
Entity name
Myxoma, intracardiac
Benign neoplasms that occur in 7 per 10,000 individuals. These slowely proliferating lesions arise from subendocardial pluripotent primitive mesenchymal cells, which can differentiate within myxomas along a variety of lineages including epithelial, hematopoietic, and muscular.
Life span is decreased in patients with myxomas. Morbidity and mortality are the result of embolic stroke, heart failure due to intracardiac obstruction, and rheumatologic symptoms attributed to myxoma-mediated production of IL-6.
Limited data; 15 cases of myxomas contained clonal numerical and structural abnormalities including telomeric associations.
Hybrid gene
Mutations of PRKARIA detected in the coding region of the gene, exons 5, 7 and 8.
No somatic mutations were detected in cardiac myxomas; haploinsufficiency of PRKARIA and a reversal of the ratio of RIA to R2B have been proposed may contribute in tumorigenesis.
Entity name
Papillary thyroid carcinoma
Reciprocal translocation between chromosomes 10 and 17
Hybrid gene
RET/PTC2 is formed by the fusion of the RET tyrosine kinase domain with part of the RI-alpha regulatory subunit
Fusion protein
The fusion of the RET tyrosine kinase domain with a portion of the RIA gene leads to the expression of RET in the thyroid cells, where it is normally transcriptionally silent.


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Pubmed IDLast YearTitleAuthors
145003622003Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.Bertherat J et al
81870851994Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas.Bongarzone I et al
18323371991The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase.Boshart M et al
98434631998Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.Casey M et al
109740262000Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex.Casey M et al
123620312002Genetic testing and genetic counselling in hypertrophic cardiomyopathy: the French experience.Charron P et al
120211652002Perspective: lessons learned from molecular genetic studies of thyroid cancer--insights into pathogenesis and tumor-specific therapeutic targets.Fagin JA et al
24060251990PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas.Grieco M et al
124247092002Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.Groussin L et al
18890881991Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A.Jones KW et al
109732562000Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.Kirschner LS et al
124574482002High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas.Lam KY et al
97686761998RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas.Learoyd DL et al
122037832002Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer.Sandrini F et al
120959362002Molecular mechanisms of RET activation in human cancer.Santoro M et al

Other Information

Locus ID:

NCBI: 5573
MIM: 188830
HGNC: 9388
Ensembl: ENSG00000108946


dbSNP: 5573
ClinVar: 5573
TCGA: ENSG00000108946


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Insulin signaling pathwayKEGGko04910
Insulin signaling pathwayKEGGhsa04910
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
DAG and IP3 signalingREACTOMER-HSA-1489509
CaM pathwayREACTOMER-HSA-111997
Calmodulin induced eventsREACTOMER-HSA-111933
PKA-mediated phosphorylation of CREBREACTOMER-HSA-111931
PKA activationREACTOMER-HSA-163615
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
EGFR interacts with phospholipase C-gammaREACTOMER-HSA-212718
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PLC-gamma1 signallingREACTOMER-HSA-167021
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by GPCRREACTOMER-HSA-372790
Opioid SignallingREACTOMER-HSA-111885
G-protein mediated eventsREACTOMER-HSA-112040
PLC beta mediated eventsREACTOMER-HSA-112043
Ca-dependent eventsREACTOMER-HSA-111996
DARPP-32 eventsREACTOMER-HSA-180024
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog 'off' stateREACTOMER-HSA-5610787
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Aquaporin-mediated transportREACTOMER-HSA-445717
Vasopressin regulates renal water homeostasis via AquaporinsREACTOMER-HSA-432040
Integration of energy metabolismREACTOMER-HSA-163685
Regulation of insulin secretionREACTOMER-HSA-422356
Glucagon-like Peptide-1 (GLP1) regulates insulin secretionREACTOMER-HSA-381676
Glucagon signaling in metabolic regulationREACTOMER-HSA-163359
PKA activation in glucagon signallingREACTOMER-HSA-164378

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
193723762009Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans.299
192932682009Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes.97
192932682009Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes.97
167283942006Epac1 and cAMP-dependent protein kinase holoenzyme have similar cAMP affinity, but their cAMP domains have distinct structural features and cyclic nucleotide recognition.63
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
203585822010Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update.55
167283922006Delineation of type I protein kinase A-selective signaling events using an RI anchoring disruptor.54
153315772004Minireview: PRKAR1A: normal and abnormal functions.52
124247092002Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.50
205073462010The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes.48


Constantine A Stratakis ; Ludmila Matyakhina

PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1))

Atlas Genet Cytogenet Oncol Haematol. 2004-10-01

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