Genetic disorders of membrane transport. V. The epithelial sodium channel and its implication in human diseases

The epithelial Na+ channel (ENaC) controls the rate-limiting step in the process of transepithelial Na+ reabsorption in the distal nephron, the distal colon, and the airways. Hereditary salt-losing syndromes have been ascribed to loss of function mutations in the alpha-, beta-, or gamma-ENaC subunit genes, whereas gain of function mutations (located in the COOH terminus of the beta- or gamma-subunit) result in hypertension due to Na+ retention (Liddle's syndrome). In mice, gene-targeting experiments have shown that, in addition to the kidney salt-wasting phenotype, ENaC was essential for lung fluid clearance in newborn mice. Disruption of the alpha-subunit resulted in a complete abolition of ENaC-mediated Na+ transport, whereas knockout of the beta- or gamma-subunit had only minor effects on fluid clearance in lung. Disruption of each of the three subunits resulted in a salt-wasting syndrome similar to that observed in humans.