Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension
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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.
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In aldosterone-producing adenomas without KCNJ5 mutations, ATP1A1 abnormalities were found in 5.2% and ATP2B3 abnormalities in 1.6%, and these mutations were associated with increased plasma aldosterone concentrations and lower potassium concentrations than cases without the mutation.
“In aldosterone-producing adenomas that did not have KCNJ5 mutations, abnormalities in ATP1A1 (encoding a Na+/K+ ATPase α subunit) were found in 5.2% and of ATP2B3 (encoding a Ca2+ ATPase) in 1.6%, with these mutations associated with increased plasma aldosterone concentrations and lower potassium concentrations than cases without the mutation (156).”
From Adrenal incidentaloma (2020) · cites this paper as [156]
Somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in aldosterone-producing adenoma tissue, altogether accounting for most cases.
“Similarly, somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in APA tissue, altogether accounting for most cases (157, 158, 161–164).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [163]
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- Authors
- Beuschlein, F., Boulkroun, S., Osswald, A., Wieland, T., Nielsen, H. N., Lichtenauer, U. D., Penton, D., Schack, V. R., Amar, L., Fischer, E., Walther, A., Tauber, P., Schwarzmayr, T., Diener, S., Graf, E., Allolio, B., Samson-Couterie, B., Benecke, A., Quinkler, M., Fallo, F., Plouin, P.-F., Mantero, F., Meitinger, T., Mulatero, P., Jeunemaitre, X., Warth, R., Vilsen, B., Zennaro, M.-C., Strom, T. M., & Reincke, M.
- Affiliations
- LMU Klinikum (DE)
- Inserm (FR)
- Ludwig-Maximilians-Universität München (DE)
- Helmholtz Munich (DE)
- Aarhus University (DK)
- University of Regensburg (DE)
- Universitätsklinikum Würzburg (DE)
- Centre National de la Recherche Scientifique (FR)
- Charité – Universitätsmedizin Berlin (DE)
- University of Padua (IT)
- University of Turin (IT)
- Corresponding author
- Beuschlein, Felix
- ORCID
- Venue
- Nature Genetics
- Published
- 2013-02-17
- Volume
- 45
- Issue
- 4
- Pages
- 440-444
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2008821347
- Cited by
- 577
- References
- 22
- Citations by year
- 2026: 33 · 2025: 29 · 2024: 21 · 2023: 34 · 2022: 38 · 2021: 47 · 2020: 34 · 2019: 50 · 2018: 40 · 2017: 55 · 2016: 54 · 2015: 60 · 2014: 47 · 2013: 31
- FWCI
- 50.44
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- Lundbeckfonden (R118-2012-11726)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- aldosterone-producing adenoma, ATP1A1, ATP2B3, somatic mutations, secondary hypertension, primary aldosteronism, Na+/K+-ATPase, Ca2+-ATPase, KCNJ5, ion homeostasis, adrenal adenoma, plasma aldosterone, hypokalemia
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Adrenal Cortex Neoplasms, Aldosterone, Calcium, Cells, Cultured, Electrophysiology, Humans, Hypertension, Immunoenzyme Techniques, Mutation, Potassium, Sodium, Adrenocortical Adenoma, Plasma Membrane Calcium-Transporting ATPases
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