title: A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.
abstract: Disorders of water balance are among the most common and morbid of the electrolyte disturbances, and are reflected clinically as abnormalities in the serum sodium concentration. The transient receptor potential vanilloid 4 (TRPV4) channel is postulated to comprise an element of the central tonicity-sensing mechanism in the mammalian hypothalamus, and is activated by hypotonic stress in vitro. A nonsynonymous polymorphism in the TRPV4 gene gives rise to a Pro-to-Ser substitution at residue 19. We show that this polymorphism is significantly associated with serum sodium concentration and with hyponatremia (serum sodium concentration < or =135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the TRPV4(P19S) allele relative to the wild-type allele. Subjects with the minor allele were 2.4-6.4 times as likely to exhibit hyponatremia as subjects without the minor allele (after inclusion of key covariates). Consistent with these observations, a human TRPV4 channel mutated to incorporate the TRPV4(P19S) polymorphism showed diminished response to hypotonic stress (relative to the wild-type channel) and to the osmotransducing lipid epoxyeicosatrienoic acid in heterologous expression studies. These data suggest that this polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis.
authors: Department of Medicine, Divisions of Nephrology and Hypertension, and Endocrinology and Metabolism, Oregon Health and Science University, Portland, OR 97239, USA.
authors: Wei
authors: W
authors: Tian
authors: Yi
authors: Y
authors: Fu
authors: Anna
authors: A
authors: Garcia-Elias
authors: José M
authors: JM
authors: Fernández-Fernández
authors: Rubén
authors: R
authors: Vicente
authors: Patricia L
authors: PL
authors: Kramer
authors: Robert F
authors: RF
authors: Klein
authors: Robert
authors: R
authors: Hitzemann
authors: Eric S
authors: ES
authors: Orwoll
authors: Beth
authors: B
authors: Wilmot
authors: Shannon
authors: S
authors: McWeeney
authors: Miguel A
authors: MA
authors: Valverde
authors: David M
authors: DM
authors: Cohen
mesh_terms: D000368:Aged; D000483:Alleles; D000818:Animals; D015331:Cohort Studies; D006801:Humans; D007010:Hyponatremia / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D010024:Osteoporosis / Q000235:genetics; D011110:Polymorphism, Genetic; D011392:Proline / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D012737:Sex Factors; D050916:TRPV Cation Channels / Q000235:genetics* / Q000502:physiology*
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D012694:Serine; D011392:Proline