Aldosterone-Producing Lesions Harboring ATP1A1 and ATP2B3 Mutations: An International Multicenter Study

BACKGROUND: Somatic aldosterone-driver mutations are identified in >90% of patients with primary aldosteronism undergoing adrenalectomy, and they display distinct demographic clustering. ATP1A1 and ATP2B3 mutations, encoding the Na + /K + ATPase α1 subunit and the Ca 2+ ATPase 3, respectively, are relatively rare and are often grouped as ATPase mutations. Differences in their clinical and biochemical phenotypes remain understudied. METHODS: This international collaboration of 16 centers included patients with primary aldosteronism harboring pathogenic variants in ATP1A1 and ATP2B3 . Clinical data were collected from medical records. Where available, we compared histopathologic features and steroid profiles (from peripheral and adrenal vein samples) by liquid chromatography-tandem mass spectrometry. RESULTS: We included 300 patients (mean age, 57±11 years; 85% men) with aldosterone-producing lesions harboring ATP1A1 (204) and ATP2B3 (96) mutations. Age and sex distributions were similar. ATP2B3 mutations were associated with lower serum potassium, higher lateralization indices, and stronger contralateral suppression. Postoperative biochemical cure was achieved in 96% of patients with ATP2B3 mutations versus 83% of those with ATP1A1 mutations ( P =0.02). Multiple CYP11B2-positive lesions were observed in 47% of ATP1A1 versus 27% of ATP2B3 cases ( P =0.03). Baseline peripheral steroid profiling was available in 126 patients (84 with ATP1A1 and 42 with ATP2B3 ) and showed higher aldosterone concentrations in the ATP2B3 group (median [interquartile range], 31 ng/dL [20–43] versus 23 ng/dL [11–38]; P =0.03). CONCLUSIONS: ATP ase mutations are most common in middle-aged men with lateralized primary aldosteronism. Compared with ATP1A1 , ATP2B3 mutations are associated with a more severe primary aldosteronism phenotype, stronger lateralization, and higher rates of single aldosterone-producing lesions and postoperative biochemical cure.

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Journal
Hypertension
Published
2026-10-13
DOI
https://doi.org/10.1161/hypertensionaha.126.27798
Primary Topic
Hormonal Regulation and Hypertension
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article
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article

Aldosterone-Producing Lesions Harboring ATP1A1 and ATP2B3 Mutations: An International Multicenter Study

Frederike Butz, James Matthew Luther, Markus Kroiss, Fumitoshi Satoh et al.
Hypertension
Hormonal Regulation and Hypertension
article

Aldosterone-Producing Lesions Harboring ATP1A1 and ATP2B3 Mutations: An International Multicenter Study

Frederike Butz, James Matthew Luther, Markus Kroiss, Fumitoshi Satoh, Maria‐Christina Zennaro, Michael Stowasser, Madson Queiroz Almeida, Vin‐Cent Wu, Ute I. Scholl, Troy Hai Kiat Puar, Silas Allen Culver, Tracy Ann Williams, Jinbo Hu, Irina Bancos, Heather Wachtel, Adina F. Turcu, Juilee Rege, Matthias Oettle, Yuta Tezuka, Stéphanie Baron, Debbie L. Cohen, William F. Young, Augusto G Guimaraes, Anand Vaidya, Amir Hekmat Hamrahian, Ismail Osman, Aaron M. Udager, Laurence Amar, William E. Rainey, Peeradon Vibhatavata, Fabio Luiz Fernandes-Rosa, Desmaré van Rooyen, Benjamin Pariente, Chun-Yi Wu, Yueting Liu
article en

Abstract

BACKGROUND: Somatic aldosterone-driver mutations are identified in >90% of patients with primary aldosteronism undergoing adrenalectomy, and they display distinct demographic clustering. ATP1A1 and ATP2B3 mutations, encoding the Na + /K + ATPase α1 subunit and the Ca 2+ ATPase 3, respectively, are relatively rare and are often grouped as ATPase mutations. Differences in their clinical and biochemical phenotypes remain understudied. METHODS: This international collaboration of 16 centers included patients with primary aldosteronism harboring pathogenic variants in ATP1A1 and ATP2B3 . Clinical data were collected from medical records. Where available, we compared histopathologic features and steroid profiles (from peripheral and adrenal vein samples) by liquid chromatography-tandem mass spectrometry. RESULTS: We included 300 patients (mean age, 57±11 years; 85% men) with aldosterone-producing lesions harboring ATP1A1 (204) and ATP2B3 (96) mutations. Age and sex distributions were similar. ATP2B3 mutations were associated with lower serum potassium, higher lateralization indices, and stronger contralateral suppression. Postoperative biochemical cure was achieved in 96% of patients with ATP2B3 mutations versus 83% of those with ATP1A1 mutations ( P =0.02). Multiple CYP11B2-positive lesions were observed in 47% of ATP1A1 versus 27% of ATP2B3 cases ( P =0.03). Baseline peripheral steroid profiling was available in 126 patients (84 with ATP1A1 and 42 with ATP2B3 ) and showed higher aldosterone concentrations in the ATP2B3 group (median [interquartile range], 31 ng/dL [20–43] versus 23 ng/dL [11–38]; P =0.03). CONCLUSIONS: ATP ase mutations are most common in middle-aged men with lateralized primary aldosteronism. Compared with ATP1A1 , ATP2B3 mutations are associated with a more severe primary aldosteronism phenotype, stronger lateralization, and higher rates of single aldosterone-producing lesions and postoperative biochemical cure.

Hypertension
Thammasat University (TH), Mayo Clinic (US), Johns Hopkins University (US), Inserm (FR), Tohoku University (JP), Université Paris Cité (FR), University of Michigan (US), University of Virginia Health System (US), Johns Hopkins Medicine (US), Princess Alexandra Hospital (AU), Changi General Hospital (SG), LMU Klinikum (DE), Humboldt-Universität zu Berlin (DE), Tohoku University Hospital (JP), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Européen Georges-Pompidou (FR), Hôpital Européen (FR), Duke-NUS Medical School (SG), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Paris Cardiovascular Research Center (FR), National Taiwan University Hospital (TW), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania Health System (US), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Mayo Clinic in Florida (US), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Chongqing Medical University (CN), Vanderbilt University Medical Center (US)
Openalex Percentile: Top 12%
Hormonal Regulation and Hypertension
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