A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III

Silvia Monticone, Namita G. Hattangady, David Penton, Carlos M. Isales, Michael A. Edwards, Tracy A. Williams, Christina Sterner, Richard Warth, Paolo Mulatero, William E. Rainey

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


Context: Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms. Mutations in the KCNJ5 gene, which encodes the inward rectifier K+ channel 4 (G protein-activated inward rectifier K+ channel 4, Kir3.4), cause familial hyperaldosteronism type III (FH-III) and are involved in the pathogenesis of sporadic aldosterone-producing adenomas. Objective: The objective of the study was to characterize the effects of a newly described KCNJ5 mutation in vitro. Patients and Methods: The index case is a 62-year-old woman affected by primary aldosteronism, who underwent left adrenalectomy after workup for adrenal adenoma. Exon 1 of KCNJ5 was PCR amplified from adrenal tissue and peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 expression. Results: KCNJ5 sequencing in the index case revealed a new p.Y152C germline mutation; interestingly, the phenotype of the patient was milder than most of the previously described FH-III families. The tyrosine-to-cysteine substitution resulted in pathologicalNa+permeability, cellmembrane depolarization, and disturbed intracellular Ca2+ homeostasis, effects similar, albeit smaller, to the ones demonstrated for other KCNJ5 mutations. Gene expression studies revealed an increased expression of CYP11B2 and its transcriptional regulator NR4A2 in HAC15 adrenal cells overexpressing KCNJ5 Y152C compared to the wild-type channel. The effect was clearly Ca2+-dependent, because it was abolished by the calcium channel blocker nifedipine. Conclusions: Herein we describe a new germline mutation in KCNJ5 responsible for FH-III.

Original languageEnglish (US)
Pages (from-to)E1861-E1865
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 1 2013

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


Dive into the research topics of 'A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III'. Together they form a unique fingerprint.

Cite this