title: Microinsertions in PRKACA cause activation of the protein kinase A pathway in cardiac myxoma.
abstract: Cardiac myxoma is the most common cardiac tumour. Most lesions occur sporadically, but occasional lesions develop in patients with Carney complex, a syndrome characterized by cardiac myxoma, spotty pigmentation, and endocrine overactivity. Two-thirds of patients with Carney complex harbour germline mutations in PRKAR1A, which encodes the type I regulatory subunit of protein kinase A (PKA). Most studies have not found a mutation in PRKAR1A in sporadic cardiac myxoma cases. Recent studies identified frequent mutations in PRKACA, which encodes the catalytic subunit of PKA, in cortisol-secreting adrenocortical adenoma cases. To determine whether the PRKACA mutation is involved in the tumourigenesis of cardiac myxoma, we performed Sanger sequencing of 41 specimens of sporadic cardiac myxoma to test for the presence of mutations in the coding regions and intron-exon boundaries of PRKACA. Mutations were identified in four cases (9.7%). In contrast to the point mutations identified in adrenocortical adenoma, all mutations were in-frame microinsertions of 18-33 bp clustered in exons 7 and 8. The mutated PRKACA proteins lost their ability to bind to PRKAR1A, and thereby lead to constitutive activation of the PKA pathway. Together with previous reports of PRKAR1A mutations in syndromic cardiac myxoma, our study demonstrates the importance of the PKA pathway in the tumourigenesis of cardiac myxoma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Tseng
authors.affiliation: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taiwan, Taiwan.|Department of Oral Hygiene, Hsin-Sheng College of Medical Care and Management, Taoyuan, Taiwan.
authors.forename: Wei-Ju
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taiwan, Taiwan.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Jhuang
authors.affiliation: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taiwan, Taiwan.
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Hung-Pin
authors.initials: HP
authors.lastname: Hsu
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taiwan, Taiwan.
authors.forename: Yung-Ming
authors.identifier: 0000-0002-9986-7194
authors.initials: YM
authors.lastname: Jeng
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics*; D002648:Child; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006338:Heart Neoplasms / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D009232:Myxoma / Q000201:enzymology / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human
keywords: PRKACA; cardiac myxoma; mutation; protein kinase A