{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:55:58Z","timestamp":1790816158326,"version":"4.1.0"},"reference-count":32,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:sec><jats:title>Context:<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective:<\/jats:title><jats:p>The objective of the study was to investigate PRKACA somatic variants identified in APA cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design:<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting and Patients:<\/jats:title><jats:p>APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2016-1700","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T17:02:40Z","timestamp":1465318960000},"page":"3010-3017","source":"Crossref","is-referenced-by-count":52,"title":["PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas"],"prefix":"10.1210","volume":"101","author":[{"given":"Yara","family":"Rhayem","sequence":"first","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, D-80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis G.","family":"Perez-Rivas","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, D-80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dietz","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, D-80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Bathon","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology (K.B., D.C.), D-97070 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Gebhard","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, D-80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Riester","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, D-80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Mauracher","sequence":"additional","affiliation":[{"name":"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 Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, D-80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso","family":"Gomez-Sanchez","sequence":"additional","affiliation":[{"name":"Division of Endocrinology (C.G.-S.), G.V. 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correctable forms, in centers from five continents","volume":"89","author":"Mulatero","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071616265327200_B3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1530\/EJE-11-1013","article-title":"Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies","volume":"167","author":"Hannemann","year":"2012","journal-title":"Eur J Endocrinol"},{"key":"2020071616265327200_B4","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.jacc.2005.01.015","article-title":"Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism","volume":"45","author":"Milliez","year":"2005","journal-title":"J Am Coll Cardiol"},{"key":"2020071616265327200_B5","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1126\/science.1198785","article-title":"K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension","volume":"331","author":"Choi","year":"2011","journal-title":"Science"},{"key":"2020071616265327200_B6","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/ng.2550","article-title":"Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension","volume":"45","author":"Beuschlein","year":"2013","journal-title":"Nat Genet"},{"key":"2020071616265327200_B7","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/ng.2695","article-title":"Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism","volume":"45","author":"Scholl","year":"2013","journal-title":"Nat Genet"},{"key":"2020071616265327200_B8","doi-asserted-by":"crossref","first-page":"e06315","DOI":"10.7554\/eLife.06315","article-title":"Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism","volume":"4","author":"Scholl","year":"2015","journal-title":"Elife"},{"key":"2020071616265327200_B9","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/ng.2716","article-title":"Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension","volume":"45","author":"Azizan","year":"2013","journal-title":"Nat Genet"},{"key":"2020071616265327200_B10","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nrm3432","article-title":"Assembly of allosteric macromolecular switches: lessons from PKA","volume":"13","author":"Taylor","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"11","key":"2020071616265327200_B11","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1056\/NEJMoa1310359","article-title":"Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome","volume":"370","author":"Beuschlein","year":"2014","journal-title":"N Engl J 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Endocrinol"},{"key":"2020071616265327200_B15","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.humpath.2014.09.005","article-title":"Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes","volume":"46","author":"Carney","year":"2015","journal-title":"Hum Pathol"},{"key":"2020071616265327200_B16","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1097\/HJH.0b013e32834937f3","article-title":"Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study","volume":"29","author":"Fallo","year":"2011","journal-title":"J Hypertens"},{"key":"2020071616265327200_B17","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1530\/EJE-10-1070","article-title":"Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism","volume":"164","author":"Spath","year":"2011","journal-title":"Eur J Endocrinol"},{"key":"2020071616265327200_B18","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1210\/jc.2008-1851","article-title":"Risk factors associated with a low glomerular filtration rate in primary aldosteronism","volume":"94","author":"Reincke","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071616265327200_B19","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1210\/jc.2008-0104","article-title":"Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline","volume":"93","author":"Funder","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071616265327200_B20","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1161\/HYPERTENSIONAHA.115.06186","article-title":"Genotype-specific steroid profiles associated with aldosterone-producing adenomas","volume":"67","author":"Williams","year":"2016","journal-title":"Hypertension"},{"key":"2020071616265327200_B21","doi-asserted-by":"crossref","first-page":"5680","DOI":"10.1038\/ncomms6680","article-title":"PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit","volume":"5","author":"Calebiro","year":"2014","journal-title":"Nat Commun"},{"key":"2020071616265327200_B22","doi-asserted-by":"crossref","first-page":"e34838","DOI":"10.1371\/journal.pone.0034838","article-title":"Identification and characterization of novel mutations in the human gene encoding the catalytic subunit C\u03b1 of protein kinase A (PKA)","volume":"7","author":"Soberg","year":"2012","journal-title":"PLoS One"},{"key":"2020071616265327200_B23","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.mce.2013.11.022","article-title":"Development of monoclonal antibodies against human CYP11B1 and 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Histidine 87 in the catalytic subunit complements serine 99 in the type I regulatory subunit","volume":"269","author":"Cox","year":"1994","journal-title":"J Biol Chem"},{"key":"2020071616265327200_B26","doi-asserted-by":"crossref","first-page":"9011","DOI":"10.1073\/pnas.0802403105","article-title":"Congenital disease SNPs target lineage specific structural elements in protein kinases","volume":"105","author":"Torkamani","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071616265327200_B27","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1126\/science.1146447","article-title":"PKA type II\u03b1 holoenzyme reveals a combinatorial strategy for isoform diversity","volume":"318","author":"Wu","year":"2007","journal-title":"Science"},{"key":"2020071616265327200_B28","doi-asserted-by":"crossref","first-page":"16203","DOI":"10.1021\/bi00049a036","article-title":"Kinetic analysis of cAMP-dependent protein kinase: mutations at histidine 87 affect peptide binding and pH dependence","volume":"34","author":"Cox","year":"1995","journal-title":"Biochemistry"},{"key":"2020071616265327200_B29","doi-asserted-by":"crossref","first-page":"E900","DOI":"10.1210\/jc.2014-4167","article-title":"Primary aldosteronism and ARMC5 variants","volume":"100","author":"Zilbermint","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071616265327200_B30","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1507\/endocrj.K10E-402","article-title":"Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome","volume":"58","author":"Hiraishi","year":"2011","journal-title":"Endocr J"},{"key":"2020071616265327200_B31","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1507\/endocrj.EJ14-0282","article-title":"Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (PRKACA) gene in Japanese patients with several adrenal adenomas secreting cortisol","volume":"61","author":"Nakajima","year":"2014","journal-title":"Endocr J"},{"key":"2020071616265327200_B32","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1530\/EJE-14-1113","article-title":"PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases","volume":"172","author":"Thiel","year":"2015","journal-title":"Eur J Endocrinol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/101\/8\/3010\/10427454\/jcem3010.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/101\/8\/3010\/10427454\/jcem3010.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T05:10:21Z","timestamp":1656652221000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/101\/8\/3010\/2835024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,1]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2016-1700","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,1]]}}}