Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3

Pseudohypoaldosteronism type 1 (PHA-1) is a rare genetic disease caused by aldosterone resistance, characterized by severe sodium loss, hyperkalemia, dehydration, and vomiting. The Epithelial Na⁺ Channel (ENaC) is a cation channel that constitutes the rate-limiting step of transepithelial Na⁺ transport in many tissues and regulates blood volume and pressure. Mutations in any of its subunits (α, β, or γ) have been shown to cause PHA-1B. The present investigation is a case study of a 4-month-old female born to consanguineous parents with symptoms suggestive of a form of PHA-1. The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis. Whole exome sequencing, conducted to identify genetic variants, revealed a variant of uncertain significance, the homozygous missense mutation c.1594G > A, p. Gly532Ser in the <i>SCNN1G</i> gene, associated with PHA-1B3. To investigate the functional impact of this mutation, <i>in vitro</i> electrophysiological and biochemical studies were performed with wild type αβγ and mutant αβγG532S-ENaC. This analysis showed that the γG532S mutation reduced, but did not suppress ENaC expression and activity. The functional observation explains the mild phenotype of this novel <i>SCNN1G</i> mutation, which contrasts with the typically severe presentation of autosomal recessive PHA-1B. In our case, the patient showed a positive clinical response to sodium chloride supplementation alone. These findings suggest that certain missense mutations in <i>SCNN1G</i> may result in a milder disease course, underscoring the importance of functional studies in understanding genotype-phenotype correlations in PHA-1.