LAUSR

While single-nucleotide variants (SNV) in ENaC coding region occur throughout functional domains, only a few SNVs exhibit pathophysiological phenotypes with mendelian inheritance. Since a SNV that alters ENaC’s ability to sense extracellular Na⁺ has been linked to hypertension, we hypothesize that other ENaC SNVs that alter channel activity will also affect blood pressure. To identify novel low-frequency ENaC SNVs that change ENaC activity, we heterologously expressed human ENaC gamma subunit variants together with wildtype alpha and beta subunits in Xenopus oocytes. We performed two-electrode-voltage clamp (TEVC) to record amiloride-sensitive currents of these channels. We characterized rare human SNVs found in multiple genomic databases covering various γENaC domains. Among the selected SNVs, we identified three gain-of-function variants (γV110I, γG149A, γV619L) with significantly greater amiloride sensitive currents (P<0.001, n=25~55) than wildtype channels. In addition, two loss-of-function variants (γG58R, γH280R) displayed significantly decreased currents (P<0.001, n=20~25) than wildtype channels. Future studies investigate the functional effects of these SNVs by assessing the gating behavior and surface expression of these channels. These data suggests that: Although low in prevalence but high in coverage throughout the ENaC coding region, rare SNVs directly modify the channel function. Our results add the growing list of human ENaC variants that alter channel activity and could impact blood pressure in humans. National Institutes of Health Grants R01 HL147818 and P30 DK079307 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.