The size of the original pedigree and careful clinical assessment of the members at risk [2] demonstrated that Liddle syndrome is an autosomal dominant disorder, and also provided the material required for genetic linkage analysis that permitted the identification the causal mutation in the beta subunit of the amiloridesensitive Na+ channel [6]. The subunits of the epithelial sodium channel (ENaC) complex have been defined by expression cloning in the Xenopus oocyte expression system, were recognized as important candidate genes for the cause of Liddle syndrome at the time of the initial description of the structure and function of the channel subunits by Canessa and Rossier [13, 14]. The ENaC complex is composed of three homologous subunits, each of which has two membrane spanning regions and a large extracellular domain with glycosylation sites and cysteine-rich regions. The N!-and C!-terminal domains of each subunit are located in the cytoplasm, but comprise relatively minor amounts of the protein