PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas.
Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing 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.



The objective of the study was to investigate PRKACA somatic variants identified in APA cases.



Identification of PRKACA somatic 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.



APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution.



PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, 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 syndrome was present 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.



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.
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Yara
Y
Rhayem
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Luis G
LG
Perez-Rivas
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Anna
A
Dietz
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Kerstin
K
Bathon
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Christian
C
Gebhard
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Anna
A
Riester
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Brigitte
B
Mauracher
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Celso
C
Gomez-Sanchez
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Graeme
G
Eisenhofer
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Thomas
T
Schwarzmayr
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Davide
D
Calebiro
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Tim M
TM
Strom
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Martin
M
Reincke
Department of Endocrine Research (Y.R., L.G.P.-R., A.D., C.G., A.R., B.M., M.R., F.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany; Institute of Pharmacology and Toxicology (K.B., D.C.) and Rudolf Virchow Center for Experimental Biomedicine (D.C.), University of Würzburg, D-97070 Würzburg, Germany; Division of Endocrinology (C.G.-S.), G.V. (Sonny) Montgomery Veterans Affairs Medical Center, and Department of Medicine-Endocrinology (C.G.-S.), University of Mississippi Medical Center, Jackson, Mississippi 39216; Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III (G.E.) and Institute of Human Genetics (T.S.), Technische Universität Dresden, D-01307 Dresden, Germany; and Institute of Human Genetics (T.S.), Helmholtz Zentrum München, D-85764 Munich, Germany.
Felix
F
Beuschlein
D000306:Adrenal Cortex Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D018246:Adrenocortical Adenoma / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000450:Aldosterone / Q000378:metabolism*; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism; D055442:Metabolome; D008875:Middle Aged; D020125:Mutation, Missense
D000450:Aldosterone; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human