Disorders of the epithelial Na+ channel in Liddle's syndrome and autosomalrecessive pseudohypoaldosteronism type 1

The epithelial Na+ channel (ENaC) is the key step in many Na+-absorptive ep ithelia, such as kidney and distal colon, that controls the overall rate of transepithelial Na+ transport. ENaC is composed of three homologous subuni ts, alpha, beta, and gamma. The alpha subunit is the key subunit for the fo rmation of a functional ion channel, while the beta and gamma subunits can greatly potentiate the level of expressed Na+ currents. ENaCs belong to the recently identified DEG/ ENaC supergene family, sharing the same basic str ucture with cytoplasmic amino and carboxy termini, two transmembrane region s, and a targe extracellular loop. The human ENaC genes have been cloned, a nd using genetic linkage analysis the involvement of ENaC gene mutations in two distinct human diseases, Liddle's syndrome and autosomal recessive pse udohypoaldosteronism type 1 (PHA-1), has been demonstrated. In Liddle's syn drome, gain-of-function mutations in the beta or gamma ENaC subunits have b een found; all identified mutations so far reside in the carboxy terminus o f the protein, either deleting or modifying the functionally important PY m otif. In PHA-1, loss-of-function mutations in the alpha, beta, or gamma sub units have been found; these mutations either truncate a significant portio n of the structure or modify an amino acid that plays an important role in channel function. In this review, our current understanding about ENaC and the pathophysiology of Liddle's syndrome and PHA-1 caused by ENaC mutations will be discussed. Copyright (C) 2000 S. Karger AG, Basel.