Protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)
381 amino acids; about 43 kDa
cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase protein kinase A (PKA), which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. PRKAR1A encodes just one of the four regulatory subunits (RIalpha); however, RIalpha 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. This protein was found to be a tissue-specific extinguisher
Most germinal mutations are null alleles; they are dispersed throughout the coding region of the gene.
Somatic mutations:many of tumors that develop in patients with Carney complex and PPNAD show loss of heterozygosity; somatic mutations in the PRKARIA gene have been reported in sporadic adrenocortical tumors. There are no mutation hot spots.
Defects in PRKAR1A are the cause of Carney complex type 1 (CNC1). CNC is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and some other tumors. Half of CNC patients show PRKARIA mutations. PRKARIA is frequently affected by bi-allelic inactivation.
Defects in PRKAR1A are the cause of primary pigmented nodular adrenocortical disease type 1 (PPNAD1). PPNAD is a rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. PPNAD1 is most often diagnosed in patients with Carney complex, but it can also be observed in patients without other manifestations or familial history. 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.
Somatic PRKAR1A mutations have been associated with sporadic adrenocortical tumor.
Defects in PRKAR1A are the cause of intracardiac myxoma. It consists in benign and slowly proliferating lesions that arise from subendocardial pluripotent primitive mesenchymal cells. These lesions can differentiate within myxomas along a variety of lineages including epithelial, hematopoietic, and muscular. Inheritance is autosomal recessive.
In papillary thyroid carcinoma, PRKAR1A gene can fuse to the RET protooncogene by gene rearrangement (t(10;17)(q11;q24) translocation) and form a thyroid tumor-specific chimeric oncogene RET-PRKAR1A. This fusion leads to the expression of RET in the thyroid cells, where it is normally transcriptionally silent.
Another translocation, t(17;17)(q21;q24),may fuse PRKAR1A to RARA in acute myeloid leukemia (AML).
References (open access):
The Carney complex gene PRKAR1A plays an essential role in cardiac development and myxomagenesis. Yin Z, Kirschner LS. Trends Cardiovasc Med. 2009 Feb;19(2):44-9.