Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity.

ABSTRACT: Mutations in genes encoding subunits of the epithelial Na+ channel (ENaC) can cause early onset familial hypertension, demonstrating the importance of this channel in modulating blood pressure. It remains unclear whether other genetic variants resulting in subtler alterations of channel function result in hypertension or altered sensitivity of blood pressure to dietary salt. This study sought to identify functional human ENaC variants to examine how these variants alter channel activity and to explore whether these variants are associated with altered sensitivity of blood pressure to dietary salt. Six-hundred participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study with salt-sensitive or salt-resistant blood pressure underwent sequencing of the genes encoding ENaC subunits. Functional effects of identified variants were examined in a Xenopus oocyte expression system. Variants that increased channel activity included three in the gene encoding the ?-subunit (?S115N, ?R476W, and ?V481M), one in the ?-subunit (?S635N), and one in the ?-subunit (?L438Q). One ?-subunit variant (?A334T) and one ?-subunit variant (?D31N) decreased channel activity. Several ?-subunit extracellular domain variants altered channel inhibition by extracellular Na+ (Na+ self-inhibition). One variant (?A334T) decreased and one (?V481M) increased cell surface expression. Association between these variants and salt sensitivity did not reach statistical significance. This study identifies novel functional human ENaC variants and demonstrates that some variants alter channel cell surface expression and/or Na+ self-inhibition.

SUBMITTER: Ray EC 

PROVIDER: S-EPMC5130461 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature