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Two Functional Epithelial Sodium Channel Isoforms Are Present in Rodents despite Pronounced Evolutionary Pseudogenization and Exon Fusion

  • The epithelial sodium channel (ENaC) plays a key role in salt and water homeostasis in tetrapod vertebrates. There are four ENaC subunits (α, β, γ, δ), forming heterotrimeric αβγ- or δβγ-ENaCs. While the physiology of αβγ-ENaC is well understood, for decades the field has stalled with respect to δβγ-ENaC due to the lack of mammalian model organisms. The SCNN1D gene coding for δ-ENaC was previously believed to be absent in rodents, hindering studies using standard laboratory animals. We analysed all currently available rodent genomes and discovered that SCNN1D is present in rodents but was independently lost in five rodent lineages, including the Muridae (mice and rats). The independent loss of SCNN1D in rodent lineages may be constrained by phylogeny and taxon-specific adaptation to dry habitats, however habitat aridity does not provide a selection pressure for maintenance of SCNN1D across Rodentia. A fusion of two exons coding for a structurally flexible region in the extracellular domain of δ-ENaC appeared in the Hystricognathi (a group that includes guinea pigs). This conserved pattern evolved at least 41 Ma ago and represents a new autapomorphic feature for this clade. Exon fusion does not impair functionality of guinea pig (Cavia porcellus) δβγ-ENaC expressed in Xenopus oocytes. Electrophysiological characterisation at the whole-cell and single-channel level revealed conserved biophysical features and mechanisms controlling guinea pig αβγ- and δβγ-ENaC function as compared to human orthologues. Guinea pigs therefore represent commercially available mammalian model animals that will help shed light on the physiological function of δ-ENaC.

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Document Type:Article
Author:Sean M. Gettings, Stephan Maxeiner, Maria Tzika, Matthew R. D. Cobain, Irina Ruf, Fritz Benseler, Nils Brose, Gabriela Krasteva-Christ, Greetje Vande Velde, Matthias Schönberger, Mike Althaus
Parent Title (English):Molecular Biology and Evolution
First Page:5704
Last Page:5725
Publisher:Oxford University Press (OUP)
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2021/09/07
Copyright:© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution License.
Funding Information:This work was supported by intramural seed grants (HOMFOR 2017-2019) by the Medical School of Saarland University (S.M.). M.T. was supported through an undergraduate summer studentship by the Physiological Society. M.A. receives funding from the Ministry of Culture and Science of the State of North Rhine-Westphalia (FKZ 005-2101-0144), G.K.C. received funding from the DFG (SFB-TR152/P22), and G.V.V. was supported by a G0H9818N Odysseus grant from the Research Foundation Flanders (FWO).
Keyword:ENaC; SCNN1D; delta-subunit; epithelial sodium channel; evolution; exon fusion; pseudogene; rodent
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 611 Menschliche Anatomie, Zytologie, Histologie
Entry in this database:2021/09/09
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International