Exp Clin Endocrinol Diabetes 2006; 114 - P14_181
DOI: 10.1055/s-2006-933066

The novel mutation S562P in the pore region of the epithelial sodium channel causes pseudohypoaldosteronism type 1 by modifying molecular sieving

F Riepe 1, N Krone 1, F Cachat 2, W Sippell 1, G Theintz 2, L Schild 3
  • 1University Hospital Schleswig-Holstein, Campus Kiel, Division of Paediatric Endocrinology, Department of Paediatrics, Kiel, Germany
  • 2University Hospital Lausanne, Division of Pediatric Nephrology, Department of Pediatrics, Lausanne, Switzerland
  • 3University of Lausanne, Department of Pharmacology and Toxicology, Lausanne, Switzerland

Objectives: The systemic form of pseudohypoaldosteronism type 1 (PHA1) is a rare autosomal recessive disorder with salt-wasting, hyperkalemia, metabolic acidosis, and multiorgan aldosterone unresponsiveness. PHA1 is caused by loss-of function mutations in the subunit genes of the epithelial sodium channel (ENaC). A newborn presented with hypovolemic shock secondary to diarrhea and vomiting. Laboratory investigations revealed plasma Na 125 mmol/l (133–144), K 11.4 mmol/l (3.5–5.0), plasma renin activity 44 ng/ml/h (5–25), and aldosterone 1380 pg/ml (30–140). Na also elevated in sweat (141 mmol/l) and saliva (144 mmol/l).

Methods: Genomic DNA sequence analysis of all 3 subunit genes of ENaC. Functional assessment of the mutated ENaC channel in a Xenopus laevis oocyte expression system by two-electrode voltage clamp method.

Results: The patient is homozygous for a point mutation within the SCNN1A gene (c1684T>C) predicting for an amino acid exchange (S562P) in the second transmembrane domain of the ENaC α protein. The consanguineous parents and the grandmother are heterozygous. In contrast to wild type ENaC, the S562P mutant shows no activity in the Xenopus laevis oocyte expression system in agreement with the salt-losing phenotype.

Conclusion: The function of ENaC in sodium reabsorption depends critically on its ability to discriminate between sodium and other ions like potassium or calcium. The established molecular basis for the high ionic selectivity is depending on a conserved serine residue in the second transmembrane domain of the ENaC α subunit at AA position 589 in rat, corresponding to 562 in human, which when mutated allows larger ions to pass through the channel due to a modified pore geometry. We hereby provide in vivo evidence for this model as the mutation S562P in our patient leads to a multiorgan aldosterone unresponsiveness syndrome due to inadequate molecular sieving of ENaC.