Search

Primary aldosteronism (PA) encompasses a broad, heterogeneous group of disorders including both sporadic and familial forms (familial hyperaldosteronism type I, II and III). PA is the most common form of secondary hypertension and associated with a higher rate of cardiovascular complications, compared with essential hypertension. Despite significant progress in the diagnosis and management of PA, until recently the molecular mechanisms leading to inappropriate aldosterone production were largely unknown. The introduction of next-generation sequencing has had a profound impact on the field of human genetics and has given new insight in the molecular determinants that lead to both sporadic and familial forms of PA. Here we review the recent progress toward understanding of the genetic and molecular mechanisms leading to autonomous aldosterone production in PA.

Familial hyperaldosteronism type III (FH-III) is a rare and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K(+) channel 4 (Kir3.4), underlie the molecular basis of FH-III.The objective of the study was to investigate the effects of a de novo germline KCNJ5 mutation.We describe the case of a girl who came to medical attention at the age of 2 years because of polydipsia, polyuria, and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. Genomic DNA was isolated and KCNJ5 sequenced. Human adrenocortical cells were used as an in vitro model for the functional characterization of the mutant channel.KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na(+)-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil.Herein we report the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition.

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.The objective of the study was to characterize the effects of a newly described KCNJ5 mutation in vitro.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.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 pathological Na(+) permeability, cell membrane depolarization, and disturbed intracellular Ca(2+) 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 Ca(2+)-dependent, because it was abolished by the calcium channel blocker nifedipine.Herein we describe a new germline mutation in KCNJ5 responsible for FH-III.