Abstract
CONTEXT: 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. OBJECTIVE: The objective of the study was to investigate the effects of a de novo germline KCNJ5 mutation. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.