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Published on: August 30, 2017
Microinsertions in PRKACA cause activation of the protein kinase A pathway in cardiac myxoma
I-Ching Tseng1, Wei-Ju Huang2,3, Yu-Ling Jhuang2
1Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
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.
Insights
Mutations in the PRKACA gene are linked to sporadic cardiac myxoma development. These genetic alterations activate the protein kinase A (PKA) pathway, crucial for tumor formation.
Area of Science:
- Cardiovascular Pathology
- Molecular Genetics
- Oncology
Background:
- Cardiac myxoma, the most common heart tumor, can be sporadic or part of Carney complex.
- Carney complex involves cardiac myxoma, pigmentation, and endocrine issues, often linked to PRKAR1A mutations.
- PRKACA mutations are found in adrenal tumors, prompting investigation into their role in cardiac myxoma.
Purpose of the Study:
- To investigate the potential role of PRKACA gene mutations in the development of sporadic cardiac myxoma.
- To identify specific mutation types and their location within the PRKACA gene in cardiac myxoma.
Main Methods:
- Sanger sequencing was used to analyze the coding regions and intron-exon boundaries of the PRKACA gene in 41 sporadic cardiac myxoma samples.
- Functional analysis was performed to assess the impact of identified PRKACA mutations on protein binding and pathway activation.
Main Results:
- Mutations in the PRKACA gene were identified in 9.7% (4 out of 41) of sporadic cardiac myxoma cases.
- All identified mutations were in-frame microinsertions within exons 7 and 8, distinct from point mutations in adrenal tumors.
- Mutated PRKACA proteins exhibited impaired binding to PRKAR1A, leading to constitutive activation of the protein kinase A (PKA) pathway.
Conclusions:
- The study implicates PRKACA mutations in the tumorigenesis of sporadic cardiac myxoma.
- Activation of the PKA pathway, through mutations in either PRKAR1A or PRKACA, is a key mechanism in cardiac myxoma development.
- These findings highlight the central role of the PKA signaling pathway in both syndromic and sporadic cardiac myxoma.
