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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 Ca²⁺ ATPase 3, respectively, are relatively rare and are often grouped as ATPase mutations. Differences in their clinical and biochemical phenotypes remain understudied.

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.

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).

ATPase 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.