Functional expression of a pseudohypoaldosteronism type I mutated epithelial Na+ channel lacking the pore-forming region of its alpha subunit

The autosomal recessive form of type I pseudohypoaldosteronism (PHA-I) is a n inherited salt-losing syndrome resulting from diminution-of-function muta tions in the 3 subunits of the epithelial Na+ channel (ENaC). A PHA-I stop mutation (alpha(R508stop)) of the ENaC a subunit is predicted to lack the s econd transmembrane domain and the intracellular COOH-terminus, regions of the protein involved in pore function. Nonetheless, we observed a measurabl e Na+ current in Xenopus laevis oocyes that coexpress the beta and gamma su bunits with the truncated a subunit. The mutant a was coassembled with beta and gamma subunits and was present at the cell surface at a lower density, consistent with the lower Nat current seen in oocytes with the truncated a subunit. The single-channel Na+ conductance for the mutant channel was onl y slightly decreased, and the appearance of the macroscopic currents was de layed by 48 hours with respect to wild-type. Our data suggest novel roles f or the cr,subunit in the assembly and targeting of an active channel to the cell surface, and suggest that channel pores consisting of only only the b eta and gamma subunits can provide significant residual activity. This acti vity may be sufficient to explain the absence of a severe pulmonary phenoty pe in patients with PHA-I.