TY - JOUR
T1 - PRKACA somatic mutations are rare findings in aldosterone-producing adenomas
AU - Rhayem, Yara
AU - Perez-Rivas, Luis G.
AU - Dietz, Anna
AU - Bathon, Kerstin
AU - Gebhard, Christian
AU - Riester, Anna
AU - Mauracher, Brigitte
AU - Gomez-Sanchez, Celso
AU - Eisenhofer, Graeme
AU - Schwarzmayr, Thomas
AU - Calebiro, Davide
AU - Strom, Tim M.
AU - Reincke, Martin
AU - Beuschlein, Felix
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84984705769&partnerID=8YFLogxK
U2 - 10.1210/jc.2016-1700
DO - 10.1210/jc.2016-1700
M3 - Article
AN - SCOPUS:84984705769
SN - 0021-972X
VL - 101
SP - 3010
EP - 3017
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 8
ER -