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

2004-10-01 Constantine A Stratakis , Ludmila Matyakhina Affiliation

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

Identity

HGNC

PRKAR1A

LOCATION

17q24.2

LOCUSID

5573

ALIAS

ACRDYS1,ADOHR,CAR,CNC,CNC1,PKR1,PPNAD1,PRKAR1,TSE1

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

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.

Transcription

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

Proteins

Description

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).

Expression

Ubiquitously expressed, in particular in brain, endocrine tissues, adipose tissue and bone.

Localisation

Predominantly cytoplasmic; nuclear traslocation possible.

Function

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.

Homology

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%

Mutations

Germinal

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

Somatic

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

Disease

A multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and some other tumors.

Prognosis

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.

Cytogenetics

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.

Oncogenesis

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

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.

Oncogenesis

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

Disease

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.

Oncogenesis

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

Disease

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.

Prognosis

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.

Cytogenetics

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.

Oncogenesis

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

Cytogenetics

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

RET/PTC2

Oncogenesis

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.

Breakpoints

Article Bibliography

Pubmed ID	Last Year	Title	Authors
1832337	1991	The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase.	Boshart M et al
1889088	1991	Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A.	Jones KW et al
2406025	1990	PTC 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
8187085	1994	Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas.	Bongarzone I et al
9768676	1998	RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas.	Learoyd DL et al
9843463	1998	Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.	Casey M et al
10973256	2000	Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.	Kirschner LS et al
10974026	2000	Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex.	Casey M et al
12021165	2002	Perspective: lessons learned from molecular genetic studies of thyroid cancer--insights into pathogenesis and tumor-specific therapeutic targets.	Fagin JA et al
12095936	2002	Molecular mechanisms of RET activation in human cancer.	Santoro M et al

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Other Information

Locus ID:

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

Variants:

dbSNP: 5573
ClinVar: 5573
TCGA: ENSG00000108946
COSMIC: PRKAR1A

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000108946	ENST00000358598	P10644
ENSG00000108946	ENST00000358598	B2R5T5
ENSG00000108946	ENST00000392710	X6RAV4
ENSG00000108946	ENST00000392711	P10644
ENSG00000108946	ENST00000392711	B2R5T5
ENSG00000108946	ENST00000536854	P10644
ENSG00000108946	ENST00000536854	B2R5T5
ENSG00000108946	ENST00000585427	K7EIE5
ENSG00000108946	ENST00000585608	K7EMZ6
ENSG00000108946	ENST00000585815	K7EQK3

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Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Aquaporin-mediated transport	REACTOME	R-HSA-445717
Ca-dependent events	REACTOME	R-HSA-111996
Calmodulin induced events	REACTOME	R-HSA-111933
CaM pathway	REACTOME	R-HSA-111997
DAG and IP3 signaling	REACTOME	R-HSA-1489509
DAP12 interactions	REACTOME	R-HSA-2172127
DAP12 signaling	REACTOME	R-HSA-2424491
DARPP-32 events	REACTOME	R-HSA-180024
Downstream signal transduction	REACTOME	R-HSA-186763
EGFR interacts with phospholipase C-gamma	REACTOME	R-HSA-212718

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Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
34532875	2022	Sporadic superficial angiomyxomas demonstrate loss of PRKAR1A expression.	4
34532875	2022	Sporadic superficial angiomyxomas demonstrate loss of PRKAR1A expression.	4
34889853	2022	Superficial Angiomyxomas Frequently Demonstrate Loss of Protein Kinase A Regulatory Subunit 1 Alpha Expression: Immunohistochemical Analysis of 29 Cases and Cutaneous Myxoid Neoplasms With Histopathologic Overlap.	1
34889853	2022	Superficial Angiomyxomas Frequently Demonstrate Loss of Protein Kinase A Regulatory Subunit 1 Alpha Expression: Immunohistochemical Analysis of 29 Cases and Cutaneous Myxoid Neoplasms With Histopathologic Overlap.	1
35319526	2022	Attempting to Solve the Pigmented Epithelioid Melanocytoma (PEM) Conundrum: PRKAR1A Inactivation Can Occur in Different Genetic Backgrounds (Common, Blue, and Spitz Subgroups) With Variation in Their Clinicopathologic Characteristics.	1
35319526	2022	Attempting to Solve the Pigmented Epithelioid Melanocytoma (PEM) Conundrum: PRKAR1A Inactivation Can Occur in Different Genetic Backgrounds (Common, Blue, and Spitz Subgroups) With Variation in Their Clinicopathologic Characteristics.	1
35503882	2022	Next-Generation Sequencing Reveals a New Class of Melanocytic Neoplasms With Hybrid Genomic Features of PEM Including Protein Kinase R 1 Alpha Gene Inactivation and Spitz Tumor-Defining Protein Kinase Fusions.	1
35732416	2022	Phenotypic Variability in a Family with Carney Complex Accompanied by a Novel Mutation Involving PRKAR1A.	1
36213268	2022	Association between subclinical hyperthyroidism and a PRKAR1A gene variant in Carney complex patients: A case report and systematic review.	3
38310436	2023	Somatic Mutation of PRKAR1A in Four Cases of Sporadic Cardiac Myxoma.	1

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Citation

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

Online version: http://atlasgeneticsoncology.org/gene/387