Williams, Tracy Ann and Monticone, Silvia and Schack, Vivien R. and Stindl, Julia and Burrello, Jacopo and Buffolo, Fabrizio and Annaratone, Laura and Castellano, Isabella and Beuschlein, Felix and Reincke, Martin and Lucatello, Barbara and Ronconi, Vanessa and Fallo, Francesco and Bernini, Giampaolo and Maccario, Mauro and Giacchetti, Gilberta and Veglio, Franco and Warth, Richard and Vilsen, Bente and Mulatero, Paolo (2014) Somatic ATP1A1, ATP2B3, and KCNJ5 Mutations in Aldosterone-Producing Adenomas. HYPERTENSION, 63 (1). pp. 188-195. ISSN 0194-911X, 1524-4563
Full text not available from this repository. (Request a copy)Abstract
Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes the G-protein-activated inward rectifier K+ channel 4, GIRK4, account for approximate to 40% of APAs. Additional somatic APA mutations were identified recently in 2 other genes, ATP1A1 and ATP2B3, encoding Na+/K+-ATPase 1 and Ca2+-ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in ATP1A1, ATP2B3, and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na+/K+-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg). CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations. Overexpression of Na+/K+-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of CYP11B2 gene expression and its transcriptional regulator NR4A2. Structural modeling of the Na+/K+-ATPase showed that the Gly99Arg substitution most likely interferes with the gateway to the ion binding pocket. In vitro functional assays demonstrated that Gly99Arg displays severely impaired ATPase activity, a reduced apparent affinity for Na+ activation of phosphorylation and K+ inhibition of phosphorylation that indicate decreased Na+ and K+ binding, respectively. Moreover, whole cell patch-clamp studies established that overexpression of Na+/K+-ATPase Gly99Arg causes membrane voltage depolarization. In conclusion, somatic mutations are common in APAs that result in an increase in CYP11B2 gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSMEMBRANE SEGMENT M1; K+-ATPASE; GLOMERULOSA; EXPRESSION; CELLS; HYPERTENSION; NA,K-ATPASE; SECRETION; APOPTOSIS; DIAGNOSIS; adrenal glands; aldosterone; Conn adenoma; hypertension; potassium channels; sodium-potassium-exchanging ATPase |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Richard Warth |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Dec 2019 15:11 |
| Last Modified: | 03 Dec 2019 15:11 |
| URI: | https://pred.uni-regensburg.de/id/eprint/11124 |
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