ECE2016 Guided Posters Adrenal (10 abstracts)
PRKACA somatic mutations are rare in aldosterone-producing adenomas.
Yara Rhayem 1 , Luis Gustavo Perez-Rivas 1 , Anna Dietz 1 , Kerstin Bathon 2 , Christian Gebhard 1 , Anna Riester 1 , Brigitte Mauracher 1 , Celso Gomez-Sanchez 3, , Thomas Schwarzmayr 5, , Davide Calebiro 2, , Tim M. Strom 5, , Martin Reincke 1 & Felix Beuschlein 1
1Department of Endocrine Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany; 2Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; 3Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, USA; 4Department of Medicine-Endocrinology, University of Mississippi Medical Center, Jackson, Mississippi, USA; 5Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany; 6Institute of Human Genetics, Technische Universität München, Munich, Germany; 7Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
Aldosterone-producing adenomas (APAs) are the most frequent cause of primary aldosteronism (PA). Somatic mutations of KCNJ5, ATP1A1, CACNA1D and ATP2B3 are involved in APAs formation while CTNNB1 and GNAS somatic mutations have been described in both APAs and in cortisol-producing adenomas (CPAs). In contrast, mutations of PRKACA coding for the catalytic subunit of protein kinase A have been yet only identified in CPAs.
We investigated a consecutive series of APAs from 122 Conn-patients after unilateral adrenalectomy. We performed exome or bidirectional Sanger sequencing of tumor-tissue and evaluated mutations in candidate genes as well as PRKACA. Exome sequencing revealed PRKACA somatic mutations in two APAs (1.6%). One APA carried a L206R mutation, previously described only in cortisol-producing adenoma with overt Cushing’s syndrome, while in the second case a newly identified H88D mutation was found. Both affected patients were females with hypokalemic hypertension, aldosterone excess and lateralization during adrenal venous sampling. We functionally characterized the enzymatic activity of L206R and H88D mutated PKA catalytic subunit in vitro and characterized the immunoexpression of steroidogenic enzymes in affected tissues. Functional analysis showed that the newly found H88D mutation was not associated with gain of function of PKA. Interestingly, while CYP11B2 expression was found in the H88D-mutated APA, no co-expression of CYP11B1 was present. In contrast, in the L206R-mutated APA, CYP11B1 was expressed while CYP11B2 was weak or negative. Accordingly, biochemical Cushing’s syndrome was present only in the patient with the L206R mutation. Following adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized potassium levels. We describe here for the first time PRKACA mutations in APAs as rare findings associated with PA. As cortisol co-secretion occurs in a sub-group of APAs other molecular mechanisms are likely to exist.
Volume 41
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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