AbstractHuman primary aldosteronism (PA) can be caused by mutations in several ion channel genes but mouse models replicating this condition are lacking. We now show that almost all known PA-associated CLCN2 mutations markedly increase ClC-2 chloride currents and generate knock-in mice expressing a constitutively open ClC-2 Cl⁻ channel as mouse model for PA. The Clcn2^op allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca²⁺ concentration. Clcn2^op mice display typical features of human PA, including high serum aldosterone in the presence of low renin activity, marked hypertension and hypokalemia. These symptoms are more pronounced in homozygous Clcn2^op/op than in heterozygous Clcn2^+/op mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2^+/op zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2^op mice are a valuable model to study the pathological mechanisms underlying this disease.