A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene

We investigate the genetic etiology in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of a mild and transient form of pseudohypoaldosteronism type 1 (PHA1). Twelve patients with PHA1 from four different families with clinical and bio-chemical data were analyzed. The coding regions of NR3C2 and SCNN1A genes were sequenced. Human a-epithelial sodium chan-nel (ENaC) wild-type (wt), aPhe226Cys and aPhe226Ser ENaC variants were expressed in Xenopus laevis oocytes to evaluate ENaC activity. The protein expression of a-ENaC wt and mutants was determined by Western blot. All patients were homozygotes for the p. Phe226Cys mutation of the a subunit of ENaC. In functional studies in X. laevis oocytes, p.Phe226Cys caused a significant reduction of ENaC activity (83% reduction), reduced the number of active ENaC mutant channels, and reduced the basal open probability com-pared with wt. Quantitative Western blot analysis revealed that the reduced activity of ENaC mutant channels was due to a reduced ENaC protein expression for the aPhe226Cys compared with wt. We present 12 patients from four different families with a mild and transient autosomal recessive PHA1 due to a novel homozygous missense mutation in the SCNN1A gene. Functional studies showed that the p.Phe226Cys substitution mutation in ENaC leads to a partial loss of function resulting mainly from both a decrease in the intrinsic ENaC activity and a reduction in channel expression at the protein level. The partial loss of ENaC function could explain the mild phenotype, variable expressivity, and the transient course of the disorder in these patients.NEW & NOTEWORTHY This paper demonstrates that mild autosomal recessive pseudohypoaldosteronism type 1 (PHA1) due to p.Phe226Cys missense mutation in the extracellular domain of ENaC a subunit can be transient, with phenotypic variability even with the normal sweat test, and incomplete penetrance. Functional studies explain the phenotype and denote the importance of the location on the extracellular domain of the SCNN1A p.Phe226Cys mutation for the intrinsic ENaC activity and the channel expression at the protein level.