{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Mutations in the "}, {"type": "b", "children": [{"type": "t", "text": "KCNJ5"}]}, {"type": "t", "text": " gene, which encodes the G protein–activated inwardly rectifying potassium channel (GIRK4), have emerged as a critical driver in primary aldosteronism. A series of studies have shown that both somatic and germline mutations, frequently located in or near the channel’s selectivity filter, compromise potassium selectivity and permit an aberrant influx of sodium. This “loss‐of‐selectivity” induces membrane depolarization in adrenal glomerulosa cells, thereby opening voltage‐dependent calcium channels; the resultant increase in intracellular Ca²⁺ triggers constitutive aldosterone synthesis and drives cell proliferation, ultimately contributing to the development of aldosterone-producing adenomas and familial hyperaldosteronism type III."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In clinical cohorts, patients with KCNJ5 mutations tend to be younger, predominantly female, and often display larger adenomas and higher aldosterone levels compared with nonmutated cases. Moreover, subtle differences in mutations—such as distinct amino acid substitutions at the same residue—have been associated with variable effects on cell viability and hormone output, suggesting that the precise alteration in KCNJ5 function can modulate both the severity of aldosterone excessive production and the resultant cardiovascular phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its well‐established role in adrenal pathophysiology, aberrant KCNJ5 function may also affect cardiac electrophysiology. Notably, a mutation in KCNJ5 has been linked to congenital long QT syndrome via reduced channel expression and a corresponding loss of inward rectifier activity in cardiomyocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the pivotal role of KCNJ5 in regulating membrane potential and calcium signaling. By linking ion permeability alterations to both aldosterone dysregulation and cardiac rhythm disturbances, KCNJ5 mutations provide key insights into the molecular mechanisms underlying severe hypertension and related cardiovascular conditions, and they highlight potential avenues for targeted therapeutic intervention.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Murim Choi, Ute I Scholl, Peng Yue, et al. 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