A mutation in the $\beta$-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect

R. Rauh, D. Soell, S. Haerteis, A. Diakov, V. Nesterov, B. Krueger, H. Sticht, C. Korbmacher, American Journal of Physiology-Lung Cellular and Molecular Physiology 304 (2013) L43–L55.

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Journal Article | English
Author
Rauh, Robert; Soell, Daniel; Haerteis, Silke; Diakov, Alexei; Nesterov, Viatcheslav; Krueger, BettinaLibreCat ; Sticht, Heinrich; Korbmacher, Christoph
Abstract
In some patients with atypical cystic fibrosis (CF), only one allele of the CF transmembrane conductance regulator (CFTR) gene is affected. Mutations of the epithelial sodium channel (ENaC) may contribute to the pathophysiology of the disease in these patients. To functionally characterize a mutation in the $\beta$-subunit of ENaC ($\beta$V348M) recently identified in a patient with severe CF-like symptoms (Mutesa et al. 2009), we expressed wild-type (wt) $\alpha$$\beta$$\gamma$ENaC or mutant $\alpha$$\beta$V348M$\gamma$ENaC in Xenopus laevis oocytes. The $\beta$V348M mutation stimulated amiloride-sensitive whole-cell current ($\Delta$I(ami)) by $\sim$40% but had no effect on surface expression or single-channel conductance of ENaC. Instead the mutation increased channel open probability (P(o)). Proteolytic activation of mutant ENaC by chymotrypsin was reduced compared with that of wt ENaC ($\sim$3.0-fold vs. $\sim$4.2-fold), which is consistent with the increased baseline P(o) of mutant ENaC. Similarly, the ENaC activator S3969 stimulated mutant ENaC currents to a lesser degree (by $\sim$2.6-fold) than wt ENaC currents (by $\sim$3.5-fold). The gain-of-function effect of the $\beta$V348M mutation was confirmed by whole-cell current measurements in HEK293 cells transiently transfected with wt or mutant ENaC. Computational channel modeling in combination with functional expression of different $\beta$V348 mutants in oocytes suggests that the $\beta$V348M mutation increases channel P(o) by destabilizing the closed channel state. Our findings indicate that the gain-of-function effect of the $\beta$V348M mutation may contribute to CF pathophysiology by inappropriately increasing sodium and fluid absorption in the respiratory tract.
Publishing Year
Journal Title
American Journal of Physiology-Lung Cellular and Molecular Physiology
Volume
304
Issue
1
Page
L43–L55
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Rauh R, Soell D, Haerteis S, et al. A mutation in the $\beta$-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2013;304(1):L43–L55. doi:10.1152/ajplung.00093.2012
Rauh, R., Soell, D., Haerteis, S., Diakov, A., Nesterov, V., Krueger, B., Sticht, H., & Korbmacher, C. (2013). A mutation in the $\beta$-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect. American Journal of Physiology-Lung Cellular and Molecular Physiology, 304(1), L43–L55. https://doi.org/10.1152/ajplung.00093.2012
@article{Rauh_Soell_Haerteis_Diakov_Nesterov_Krueger_Sticht_Korbmacher_2013, title={A mutation in the $\beta$-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect}, volume={304}, DOI={10.1152/ajplung.00093.2012}, number={1}, journal={American Journal of Physiology-Lung Cellular and Molecular Physiology}, publisher={American Physiological Society}, author={Rauh, Robert and Soell, Daniel and Haerteis, Silke and Diakov, Alexei and Nesterov, Viatcheslav and Krueger, Bettina and Sticht, Heinrich and Korbmacher, Christoph}, year={2013}, pages={L43–L55} }
Rauh, Robert, Daniel Soell, Silke Haerteis, Alexei Diakov, Viatcheslav Nesterov, Bettina Krueger, Heinrich Sticht, and Christoph Korbmacher. “A Mutation in the $\beta$-Subunit of ENaC Identified in a Patient with Cystic Fibrosis-like Symptoms Has a Gain-of-Function Effect.” American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 1 (2013): L43–L55. https://doi.org/10.1152/ajplung.00093.2012.
R. Rauh et al., “A mutation in the $\beta$-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 304, no. 1, pp. L43–L55, 2013, doi: 10.1152/ajplung.00093.2012.
Rauh, Robert, et al. “A Mutation in the $\beta$-Subunit of ENaC Identified in a Patient with Cystic Fibrosis-like Symptoms Has a Gain-of-Function Effect.” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 304, no. 1, American Physiological Society, 2013, pp. L43–L55, doi:10.1152/ajplung.00093.2012.

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