Familial hyperaldosteronism type III (FH-III) is a rare autosomal dominant 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), represent the molecular basis of FH-III. So far, five germline mu- tations in the KCNJ5 gene have been identified and functionally characterized in patients with FH-III. Objective of the present study was to characterized the effect of a de novo KCNJ5 germline substitution in vitro.
Design and method:
We describe the case of a girl affected by severe hyperaldosteronism. KCNJ5 gene was PCR amplified from 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 (aldosterone synthase) expression.
The index case is a Caucasian girl born to nonconsanguineous parents. She came to medical attention at the age of two 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. At the age of 19 she was on four antihypertensive medications and potassium supplements; transthoracic echocardiography revealed mildly dilated aortic root and ascending aorta without left ventricular hypertrophy. The patient consented to bilateral adrenalectomy which was performed laparoscopically. 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 on 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.