KCNJ5 – Familial Hyperaldosteronism Type III

Familial hyperaldosteronism type III (MONDO:0013359) is an autosomal dominant form of primary aldosteronism characterized by severe hypertension, hypokalemia and variable adrenal hyperplasia. The KCNJ5 gene encodes the inward rectifier potassium channel Kir3.4, which normally maintains glomerulosa membrane potential. Pathogenic variants in KCNJ5 disrupt Na+ selectivity, leading to cell depolarization, Ca2+-dependent upregulation of CYP11B2 and autonomous aldosterone synthesis.

Autosomal dominant inheritance of KCNJ5 variants is supported by four unrelated probands: a p.Tyr152Cys germline mutation (c.455A>G) in a 62-year-old woman (PMID:24037882), a de novo p.Gly151Arg substitution (c.451G>C) in an early-onset case (PMID:24819081), and two independent p.Glu145Gln events (c.433G>C) presenting in infancy and early adulthood (PMID:25322277; PMID:27403928). Segregation in two affected siblings with altered zonal CYP11B2 expression further substantiates variant pathogenicity (PMID:27793677).

Affected individuals exhibit early-onset hypertension (HP:0000822), persistent hypokalemia (HP:0002900) and polyuria (HP:0000103), with some showing polydipsia and failure to thrive. Phenotypic severity ranges from mild, spironolactone-responsive disease to massive bilateral adrenal hyperplasia refractory to medical therapy, underscoring a genotype–phenotype continuum.

In vitro electrophysiology of mutant Kir3.4 channels demonstrates impaired K+ selectivity and Na+ leak currents, causing membrane depolarization and elevated intracellular Ca2+. Overexpression of p.Tyr152Cys, p.Gly151Arg or p.Glu145Gln in HAC15 adrenal cells induces up to 3-fold increases in CYP11B2 and NR4A2 expression; these effects are abrogated by Ca2+ channel blockers such as nifedipine or verapamil (PMID:24037882; PMID:25322277).

Histopathological studies of FH-III adrenals reveal loss of normal zonation and ectopic co-expression of CYP11B2 with CYP17A1 or CYP11B1, correlating with aberrant aldosterone and hybrid steroid secretion. Immunohistochemistry confirms Kir3.4 localization with CYP11B2 in hyperplastic glomerulosa cells, aligning with the channelopathy mechanism of disease.

Collectively, four independent germline missense variants with segregation in affected relatives, robust functional assays and histological concordance fulfill ClinGen criteria for a Strong gene–disease association. KCNJ5 variant testing enables definitive diagnosis of FH-III, informs family screening and guides targeted therapy with mineralocorticoid antagonists or adrenalectomy.

Key Take-home: KCNJ5 pathogenic variants cause autosomal dominant FH-III by disrupting Kir3.4 selectivity, driving Ca2+-mediated aldosterone overproduction and early-onset hypertension.

References

• The Journal of clinical endocrinology and metabolism • 2013 • a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. PMID:24037882
• Hormone research in paediatrics • 2014 • Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature. PMID:24819081
• The Journal of clinical endocrinology and metabolism • 2015 • A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue. PMID:25322277
• The Journal of clinical endocrinology and metabolism • 2016 • A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing's Syndrome. PMID:27403928
• Molecular and cellular endocrinology • 2017 • Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3. PMID:27793677

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