title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
abstract: 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.
authors: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany. felix.beuschlein@med.uni-muenchen.de
authors: Felix
authors: F
authors: Beuschlein
authors: Sheerazed
authors: S
authors: Boulkroun
authors: Andrea
authors: A
authors: Osswald
authors: Thomas
authors: T
authors: Wieland
authors: Hang N
authors: HN
authors: Nielsen
authors: Urs D
authors: UD
authors: Lichtenauer
authors: David
authors: D
authors: Penton
authors: Vivien R
authors: VR
authors: Schack
authors: Laurence
authors: L
authors: Amar
authors: Evelyn
authors: E
authors: Fischer
authors: Anett
authors: A
authors: Walther
authors: Philipp
authors: P
authors: Tauber
authors: Thomas
authors: T
authors: Schwarzmayr
authors: Susanne
authors: S
authors: Diener
authors: Elisabeth
authors: E
authors: Graf
authors: Bruno
authors: B
authors: Allolio
authors: Benoit
authors: B
authors: Samson-Couterie
authors: Arndt
authors: A
authors: Benecke
authors: Marcus
authors: M
authors: Quinkler
authors: Francesco
authors: F
authors: Fallo
authors: Pierre-Francois
authors: PF
authors: Plouin
authors: Franco
authors: F
authors: Mantero
authors: Thomas
authors: T
authors: Meitinger
authors: Paolo
authors: P
authors: Mulatero
authors: Xavier
authors: X
authors: Jeunemaitre
authors: Richard
authors: R
authors: Warth
authors: Bente
authors: B
authors: Vilsen
authors: Maria-Christina
authors: MC
authors: Zennaro
authors: Tim M
authors: TM
authors: Strom
authors: Martin
authors: M
authors: Reincke
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000209:etiology*; D018246:Adrenocortical Adenoma / Q000209:etiology*; D000450:Aldosterone / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004594:Electrophysiology; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D007124:Immunoenzyme Techniques; D009154:Mutation / Q000235:genetics*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics*; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: D000450:Aldosterone; D012964:Sodium; C499076:ATP1A1 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D002118:Calcium