title: Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity.
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.
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Evan C
authors: EC
authors: Ray
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Jingxin
authors: J
authors: Chen
authors: Department of Epidemiology, Tulane University, New Orleans, Louisiana.
authors: Tanika N
authors: TN
authors: Kelly
authors: Department of Epidemiology, Tulane University, New Orleans, Louisiana.|Department of Medicine, Tulane University, New Orleans, Louisiana.
authors: Jiang
authors: J
authors: He
authors: Department of Medicine, Tulane University, New Orleans, Louisiana.
authors: L Lee
authors: LL
authors: Hamm
authors: State Key Laboratory of Cardiovascular Disease, Division of Population Genetics, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Dongfeng
authors: D
authors: Gu
authors: Human Genetics Center, University of Texas School of Public Health, Houston, Texas.
authors: Lawrence C
authors: LC
authors: Shimmin
authors: Human Genetics Center, University of Texas School of Public Health, Houston, Texas.
authors: James E
authors: JE
authors: Hixson
authors: Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri.
authors: Dabeeru C
authors: DC
authors: Rao
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; shaohu@pitt.edu.
authors: Shaohu
authors: 0000-0002-7198-1702
authors: S
authors: Sheng
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.|Departments of Cell Biology and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Thomas R
authors: TR
authors: Kleyman
mesh_terms: D000483:Alleles; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics*; D053503:Epithelial Sodium Channels / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D012982:Sodium, Dietary / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D053503:Epithelial Sodium Channels; D012982:Sodium, Dietary
keywords: Genetic Epidemiology Network of Salt Sensitivity; epithelial sodium channel; salt-sensitive hypertension; sodium self-inhibition; two-electrode voltage clamp