Abstract: SA-PO0485
Gain- and Loss-of-Function Variants in Epithelial Sodium (Na+) Channel Delta Subunit
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Sheng, Shaohu, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Nickerson, Andrew, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Ray, Evan C., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Kleyman, Thomas R., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
Background
Epithelial Na+ channels (ENaCs) are trimeric complexes composed of one to three homologous subunits encoded by four distinct genes. Canonical ENaCs consist of α, β, and γ subunits, while δ subunits can form functional channels either alone or in combination with β and γ subunits. However, the physiological roles of δENaC remain unclear. In this study, we investigated the functional impact of selected missense variants in the δ subunit.
Methods
Point mutations corresponding to selected common (minor allele frequency (MAF) > 0.05), low frequency (MAF, 0.01-0.05) and rare (MAF < 0.01) variants in δ subunit were introduced into human δENaC cDNA. Wild type (WT) or mutant human δENaC were co-expressed with WT β and γ subunits in Xenopus oocytes via RNA injection. ENaC activity was assessed using two-electrode voltage clamp recordings. Amiloride-sensitive currents (0.1 mM) representing ENaC activity were measured and compared within the same baches of oocytes expressing the WT or mutant channels.
Results
Three common δENaC variants exhibited channel activity similar to WT. Among four low-frequency variants, R297C produced significantly greater amiloride-sensitive current than WT (relative current to WT: 1.7 ± 0.6, n = 40, p < 0.0001) and abolished the Na+ self-inhibition response, potentially explaining the increased activity. Of the 12 rare variants, two (G71S and C370R) showed significantly reduced amiloride-sensitive currents compared to WT (G71S: 0.2 ± 0.1, n = 46, p < 0.0001; C370R: 0.5 ± 0.4, n = 40, p < 0.0001).
Conclusion
Our results suggest that R297C is a gain-of-function low-frequency variant and G71S and C370R are loss-of-function rare variants of δENaC. These and other δENaC variants may contribute to the reported association between δENaC and blood pressure.
Funding
- NIDDK Support