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2016 ; 579
(2
): 95-132
Nephropedia Template TP
Gene
2016[Apr]; 579
(2
): 95-132
PMID26772908
show ga
The epithelial sodium channel (ENaC) is composed of three homologous subunits and
allows the flow of Na(+) ions across high resistance epithelia, maintaining body
salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney
tubules regulates extracellular fluid (ECF) volume and blood pressure by
modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and
plays an essential role in the regulation of epithelial surface liquid volume
necessary for cilial transport of mucus and gametes in the respiratory and
reproductive tracts respectively. The subunits that form ENaC (named as alpha,
beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are
members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC
orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata
(jawless vertebrates) including lampreys, followed by earliest representatives of
Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among
Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has
lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch
including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and
mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs
from 20 species and established criteria for the identification of ENaC orthologs
and paralogs, and their distinction from other members of the ENaC/Degenerin
superfamily, especially ASIC family. Differences between ENaCs and ASICs are
summarized in view of their physiological functions and tissue distributions.
Structural motifs that are conserved throughout vertebrate ENaCs are highlighted.
We also present a comparative overview of the genotype-phenotype relationships in
inherited diseases associated with ENaC mutations, including multisystem
pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease
and essential hypertension.