PRKACA somatic mutations are rare findings in aldosterone-producing adenomas

Research output: Contribution to journalArticle

Authors

  • Yara Rhayem
  • Luis G. Perez-Rivas
  • Anna Dietz
  • Kerstin Bathon
  • Christian Gebhard
  • Anna Riester
  • Brigitte Mauracher
  • Celso Gomez-Sanchez
  • Graeme Eisenhofer
  • Thomas Schwarzmayr
  • Tim M. Strom
  • Martin Reincke
  • Felix Beuschlein

Colleges, School and Institutes

External organisations

  • Ludwig-Maximilians-Universität LMU
  • University of Wurzburg
  • University of Mississippi Medical Center
  • Technische Universität Dresden
  • Helmholtz Zentrum München
  • Rudolf Virchow Center

Abstract

Context: Somatic mutations have been found causative for endocrine autonomy in aldosteroneproducing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol. Objective: The objective of the study was to investigate PRKACA somatic variants identified in APA cases. Design: Identification ofPRKACAsomatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues. Setting and Patients: APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution. Results: PRKACA somatic mutations were identified in twoAPAcases (1.6%). OneAPAcarried a newly identified p.His88Asp variant,whereasinasecondcase,ap.Leu206Argmutationwasfound, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndromewaspresent only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels. Conclusions: We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.

Details

Original languageEnglish
Pages (from-to)3010-3017
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume101
Issue number8
Publication statusPublished - 1 Aug 2016