Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Renal Physiol
2016 Nov 01;3115:F908-F914. doi: 10.1152/ajprenal.00426.2016.
Show Gene links
Show Anatomy links
Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity.
Ray EC
,
Chen J
,
Kelly TN
,
He J
,
Hamm LL
,
Gu D
,
Shimmin LC
,
Hixson JE
,
Rao DC
,
Sheng S
,
Kleyman TR
.
???displayArticle.abstract???
Mutations in genes encoding subunits of the epithelial Na+ channel (ENaC) can cause early onset familial hypertension, demonstrating the importance of this channel in modulating blood pressure. It remains unclear whether other genetic variants resulting in subtler alterations of channel function result in hypertension or altered sensitivity of blood pressure to dietary salt. This study sought to identify functional human ENaC variants to examine how these variants alter channel activity and to explore whether these variants are associated with altered sensitivity of blood pressure to dietary salt. Six-hundred participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study with salt-sensitive or salt-resistant blood pressure underwent sequencing of the genes encoding ENaC subunits. Functional effects of identified variants were examined in a Xenopus oocyte expression system. Variants that increased channel activity included three in the gene encoding the α-subunit (αS115N, αR476W, and αV481M), one in the β-subunit (βS635N), and one in the γ-subunit (γL438Q). One α-subunit variant (αA334T) and one γ-subunit variant (βD31N) decreased channel activity. Several α-subunit extracellular domain variants altered channel inhibition by extracellular Na+ (Na+ self-inhibition). One variant (αA334T) decreased and one (αV481M) increased cell surface expression. Association between these variants and salt sensitivity did not reach statistical significance. This study identifies novel functional human ENaC variants and demonstrates that some variants alter channel cell surface expression and/or Na+ self-inhibition.
Ambrosius,
Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension.
1999, Pubmed,
Xenbase
Ambrosius,
Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension.
1999,
Pubmed
,
Xenbase
Azad,
Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.
2009,
Pubmed
,
Xenbase
Baconguis,
Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes.
2012,
Pubmed
Baconguis,
X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel.
2014,
Pubmed
Beeks,
Genetic predisposition to salt-sensitivity: a systematic review.
2004,
Pubmed
Berman,
A long isoform of the epithelial sodium channel alpha subunit forms a highly active channel.
2015,
Pubmed
Büsst,
The epithelial sodium channel γ-subunit gene and blood pressure: family based association, renal gene expression, and physiological analyses.
2011,
Pubmed
Carattino,
Arachidonic acid regulates surface expression of epithelial sodium channels.
2003,
Pubmed
,
Xenbase
Chen,
Gain-of-function variant of the human epithelial sodium channel.
2013,
Pubmed
,
Xenbase
Chobanian,
Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
2003,
Pubmed
Chraïbi,
Na self inhibition of human epithelial Na channel: temperature dependence and effect of extracellular proteases.
2002,
Pubmed
,
Xenbase
Firsov,
Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach.
1996,
Pubmed
,
Xenbase
Fuchs,
Current-voltage curve of sodium channels and concentration dependence of sodium permeability in frog skin.
1977,
Pubmed
GenSalt Collaborative Research Group,
GenSalt: rationale, design, methods and baseline characteristics of study participants.
2007,
Pubmed
Gonzales,
Pore architecture and ion sites in acid-sensing ion channels and P2X receptors.
2009,
Pubmed
Hannila-Handelberg,
Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension.
2005,
Pubmed
,
Xenbase
He,
Effect of longer-term modest salt reduction on blood pressure.
2013,
Pubmed
Kashlan,
ENaC structure and function in the wake of a resolved structure of a family member.
2011,
Pubmed
Kashlan,
Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.
2015,
Pubmed
,
Xenbase
Kawasaki,
The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension.
1978,
Pubmed
Kelly,
Genomic epidemiology of blood pressure salt sensitivity.
2012,
Pubmed
Knight,
Liddle's syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage.
2006,
Pubmed
Lee,
Optimal tests for rare variant effects in sequencing association studies.
2012,
Pubmed
Lewington,
Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
2002,
Pubmed
Lim,
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
2012,
Pubmed
Liu,
Associations of epithelial sodium channel genes with blood pressure: the GenSalt study.
2015,
Pubmed
Luft,
Cardiovascular and humoral responses to extremes of sodium intake in normal black and white men.
1979,
Pubmed
Maarouf,
Novel determinants of epithelial sodium channel gating within extracellular thumb domains.
2009,
Pubmed
,
Xenbase
Mente,
Association of urinary sodium and potassium excretion with blood pressure.
2014,
Pubmed
Miller,
Blood pressure response to dietary sodium restriction in normotensive adults.
1983,
Pubmed
Miller,
Heterogeneity of blood pressure response to dietary sodium restriction in normotensive adults.
1987,
Pubmed
Miura,
Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: the Chicago Heart Association Detection Project in Industry.
2001,
Pubmed
Mozaffarian,
Global sodium consumption and death from cardiovascular causes.
2014,
Pubmed
Mueller,
Multiple residues in the distal C terminus of the α-subunit have roles in modulating human epithelial sodium channel activity.
2012,
Pubmed
,
Xenbase
Nagy,
Quantitative trait loci for blood pressure exist near the IGF-1, the Liddle syndrome, the angiotensin II-receptor gene and the renin loci in man.
1999,
Pubmed
Nguyen,
Effects of rare and common blood pressure gene variants on essential hypertension: results from the Family Blood Pressure Program, CLUE, and Atherosclerosis Risk in Communities studies.
2013,
Pubmed
Palmer,
Regulation of Na+ channels by luminal Na+ in rat cortical collecting tubule.
1998,
Pubmed
Samaha,
Functional polymorphism in the carboxyl terminus of the alpha-subunit of the human epithelial sodium channel.
2004,
Pubmed
,
Xenbase
Sheng,
Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition.
2006,
Pubmed
,
Xenbase
Shi,
Base of the thumb domain modulates epithelial sodium channel gating.
2011,
Pubmed
,
Xenbase
Shimkets,
Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.
1994,
Pubmed
Snyder,
Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.
1995,
Pubmed
,
Xenbase
Thomas,
5' heterogeneity in epithelial sodium channel alpha-subunit mRNA leads to distinct NH2-terminal variant proteins.
1998,
Pubmed
,
Xenbase
Tobin,
Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population.
2008,
Pubmed
Tong,
Functional polymorphisms in the alpha-subunit of the human epithelial Na+ channel increase activity.
2006,
Pubmed
Vehaskari,
Heritable forms of hypertension.
2009,
Pubmed
Weinberger,
Salt sensitivity of blood pressure in humans.
1996,
Pubmed
Whelton,
Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program.
2002,
Pubmed
Wong,
Genetic linkage of beta and gamma subunits of epithelial sodium channel to systolic blood pressure.
1999,
Pubmed
Yan,
Intracellular trafficking of a polymorphism in the COOH terminus of the alpha-subunit of the human epithelial sodium channel is modulated by casein kinase 1.
2007,
Pubmed
,
Xenbase
Yang,
Associations of epithelial sodium channel genes with blood pressure changes and hypertension incidence: the GenSalt study.
2014,
Pubmed
Zhao,
Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure: The GenSalt study.
2011,
Pubmed
