FH- II is the most common form of familiar hyperaldosteronism. It is clinically and biochemically indistinguishable from sporadic PA, not remediable by glucocorticoids, and diagnosis is based on the presence of two or more affected family members and autosomal dominant transmission. Patients show varying aldosterone responses on postural test and to AngII within a given family, and different PA subtypes (APA or bilateral adrenal hyperplasia) are found. Its prevalence is estimated to be 1.2% to 6% in adults with PA. The phenotypic variability of FH- II has suggested that FH- II may be associated with a variety of genetic defects. Indeed, following the first description of KCNJ5 mutations in FH- III, germline KCNJ5 gene mutations were reported in patients with a moderate phenotype resembling FH- II. In particular, affected members of three families carrying the KCNJ5 p.Gly151Glu mutation and affected members from one family carrying the KCNJ5 p.Tyr152Cys mutation exhibited a mild phenotype compatible with FH- II. Somatic mutations of KCNJ5 were also re ported in APA in patients with familial hyperaldosteronism initially diagnosed as FH- II, suggesting that in some cases FH- II may represent familial aggregation of sporadic PA, given the high frequency of PA in patients with hypertension.
The large original family with FH- II described by Stowasser et al. has been linked to a locus on chromosome 7p22, although genetic heterogeneity had been shown subsequently. It was only very recently that germline mutations in CLCN2, coding for the voltage- gated chloride channel ClC- 2, have been identified in young onset PA and in the very same family with FH- II. CLCN2 is expressed in the human and mouse adrenal cortex and is the main chloride conductor of resting glomerulosa cells. The ClC- 2 mutations affect different amino acids located in well con served domains of the protein. In particular, the ClC- 2 p.Gly24Asp mutation, found in a 9- year- old girl with PA, is located in a domain whose inactivation leads to ‘open’ ClC- 2 channels. Functional ana lysis of the mutant channel indicated that the mutation abolished the voltage- and time- dependent gating of ClC- 2, strongly increasing chloride currents at resting potential. In adrenocortical cells, this induced increased aldosterone production, which was mediated by plasma membrane depolarization, opening of voltage- gated calcium channels, increased intracellular Ca2+ concentrations and in creased expression of CYP11B2. The family described by Stowasser carried a p.Arg172Gln mutation, which was identified in four other cases; four additional mutations were identified in unrelated subjects with early- onset PA. Again, the mechanism of autonomous aldosterone production involved gain- of- function mutations, promoting cell membrane de polarization, and opening of voltage- gated calcium channels. These data identify a new genetic defect in patients with early- onset PA and a subset of FH- II and highlight the important role for chloride currents in regulating aldosterone biosynthesis.
