A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia

Wei Tian, Yi Fu, Anna Garcia-Elias, José M. Fernández-Fernández, Rubén Vicente, Patricia L. Kramer, Robert F. Klein, Robert Hitzemann, Eric S. Orwoll, Beth Wilmot, Shannon McWeeney, Miguel A. Valverde, David M. Cohen

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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 ≤135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the TRPV4P19S 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 TRPV4P19S 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.

Original languageEnglish (US)
Pages (from-to)14034-14039
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - Aug 18 2009


  • Association study
  • Cell volume regulation
  • Osmoregulation
  • Sodium
  • Transient receptor potential

ASJC Scopus subject areas

  • General


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