Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

Abstract-Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism-affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K ϩ selectivity, Na ϩ influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca 2ϩ channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype. (Hypertension. 2012;59: 235-240.) • Online Data Supplement Key Words: familial hyperaldosteronism Ⅲ endocrine hypertension Ⅲ primary aldosteronism Ⅲ aldosterone Ⅲ KCNJ5 P rimary aldosteronism (PA) is the most frequent cause of secondary hypertension, and its prevalence increases with blood pressure severity. 1 PA diagnosis is of paramount importance for the patient, not only because specific therapy is available, mineralocorticoid receptor antagonists for bilateral forms and adrenalectomy for unilateral forms, 2 but also because aldosterone causes detrimental effects on the cardiovascular system that are at least partly independent of blood pressure levels. 3,4 Current guidelines of the Endocrine Society recommend the confirmation or exclusion of PA in all groups of patients with an increased risk of the disease, 1 which include hypertensive patients with a family history of early onset hypertension or cerebrovascular events at a young age and all hypertensive first-degree relatives of patients with PA. These indications recognize the importance of testing for PA in patients at risk for familial hyperaldosteronism (FH). Three forms of FH have been described to date, named FH-I to -III. 5-8 FH-I, also known as glucocorticoid-remediable aldosteronism (GRA), is attributed to a chimeric CYP11B1/ CYP11B2 gene encoding a hybrid enzyme able to synthesize al...