. Author manuscript; available in PMC: 2023 Dec 1.

Published in final edited form as: Nat Rev Nephrol. 2023 Aug 23:10.1038/s41581-023-00753-6. doi: 10.1038/s41581-023-00753-6

Table 1. Mutations associated with primary aldosteronism.

Gene	Occurrence	Mechanism of action	Refs.
ATP1A1	Somatic in APAs	Impaired pump function and pathologically channel like-permeabilities for Na⁺, H⁺ and Ca²⁺	22,67
ATP2B3	Somatic in APAs	Channel like-permeabilities for Na⁺, H⁺ and Ca²⁺	67
CACNA1D	Germline in PASNA and somatic in APAs	Increases Ca²⁺ permeability	22,75
CACNA1H	Germline in FH-IV and somatic in APAs	Increases Ca²⁺ permeability	81,82
CADM1	Somatic in APAs	Inhibition of gap junctions and modulation of biological rhythms	95
CLCN2	Germline in FH-II and somatic in APAs	Increases Cl^- efflux	85
CTNNB1	Somatic in APAs and adrenocortical carcinomas	Prevents β-catenin degradation, which increases signalling via the TCF/LEF family	190
CYP11B1/2 hybrid gene	Germline in FH-I	Pathologically activated by ACTH via MC2R and cAMP signalling	40
GNA11 and GNAQ	Somatic in APAs	Prevents termination of G protein signalling downstream of the AT1R, leading to increased calcium release from intracellular stores Co-occurs with CTNNB1 mutations	89
KCNJ5	Germline in FH-III and somatic in APAs	Abnormal Na⁺ influx	18
SLC30A1	Somatic in APAs	Increases Zn²⁺ permeability	100

Many of the mutations cause membrane depolarization, activation of voltage-gated calcium channels, calcium influx and increased calcium signalling, which stimulates CYP11B2 expression and aldosterone production. ACTH, adrenocorticotropic hormone; APAs, aldosterone-producing adenomas; AT1R, angiotensin II type 1 receptor; FH, familial hyperaldosteronism; MC2R, melanocortin 2 receptor; PASNA, primary aldosteronism with seizures and neurological abnormalities; TCF/LEF, T cell factor/lymphoid enhancer factor.