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

Department of Medicine, Divisions of Nephrology and Hypertension, and Endocrinology and Metabolism, Oregon Health and Science University, Portland, OR 97239, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2009; 106(33):14034-9. DOI: 10.1073/pnas.0904084106
Source: PubMed


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.

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Available from: Beth Wilmot, Jul 23, 2014
    • "Within the vanilloid subfamily of TRP channels, the heatactivated TRPV1 and TRPV4 channels present a high degree of similarity in their sequence and biophysical properties (Owsianik et al., 2006). The TRPV4 cationic channel is widely distributed and participates in the transduction of osmotic (Arniges et al., 2004; Liedtke et al., 2000; Tian et al., 2009), mechanical (Andrade et al., 2005; Liedtke et al., 2003; Suzuki et al., 2003), heat (Garcia-Elias et al., 2013; Gü ler et al., 2002; Watanabe et al., 2002a), and UVB stimuli (Moore et al., 2013). TRPV1 is expressed primarily on nociceptive neurons and can be activated by capsaicin, noxious heat, and protons (Caterina et al., 1997). "
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    ABSTRACT: Functional transient receptor potential (TRP) channels result from the assembly of four subunits. Here, we show an interaction between the pre-S1, TRP, and the ankyrin repeat domain (ARD)-S1 linker domains of TRPV1 and TRPV4 that is essential for proper channel assembly. Neutralization of TRPV4 pre-S1 K462 resulted in protein retention in the ER, defective glycosylation and trafficking, and unresponsiveness to TRPV4-activating stimuli. Similar results were obtained with the equivalent mutation in TRPV1 pre-S1. Molecular dynamics simulations revealed that TRPV4-K462 generated an alternating hydrogen network with E745 (TRP box) and D425 (pre-S1 linker), and that K462Q mutation affected subunit folding. Consistently, single TRPV4-E745A or TRPV4-D425A mutations moderately affected TRPV4 biogenesis while double TRPV4-D425A/E745A mutation resumed the TRPV4-K462Q phenotype. Thus, the interaction between pre-S1, TRP, and linker domains is mandatory to generate a structural conformation that allows the contacts between adjacent subunits to promote correct assembly and trafficking to the plasma membrane. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Structure 06/2015; DOI:10.1016/j.str.2015.05.018 · 5.62 Impact Factor
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    • "TRPV4 TRPV4 is an ion channel activated both by moderate heat and cellular swelling induced by hyposmosis . Accordingly, the knockout mice have disturbances in thermosensation (Lee et al., 2005a) osmoregulation (Liedtke and Friedman, 2003), and some mutations in humans are associated with hyponatremia (Tian et al., 2009). Quite intriguingly, other mutations in TRPV4 cause a spectrum of developmental disorders (Nilius and Voets, 2013). "
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    ABSTRACT: Transient Receptor Potential (TRP) channels were discovered while analyzing visual mutants in Drosophila. The protein encoded by the transient receptor potential (trp) gene is a Ca(2+) permeable cation channel activated downstream of the phospholipase C (PLC) pathway. While searching for homologs in other organisms, a surprisingly large number of mammalian TRP channels was cloned. The regulation of TRP channels is quite diverse, but many of them are either activated downstream of PLC, or modulated by it. This review will summarize the current knowledge on regulation of TRP channels by PLC, with special focus on TRPC-s, which can be considered as effectors of PLC and the heat- and capsaicin-sensitive TRPV1, which is modulated by the PLC pathway in a complex manner.
    07/2013; 53(3). DOI:10.1016/j.jbior.2013.07.004
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    • "Four mutations in two of the six N-terminal ankyrin repeats of TRPV4 have also recently been shown to cause a spectrum of late-onset neuromuscular diseases but not skeletal dysplasia [11], [12], [13], indicating that SD and these neuromuscular diseases arise by different mechanisms [14]. This report covers only the mutations causing skeletal dysplasias and is not concerned with the four alleles causing neuromuscular disease nor the P19S polymorphism, which loosely correlate with serum hyponatremia [15] and chronic obstructive pulmonary disease [16]. "
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    ABSTRACT: TRPV4 is a mechanically activated Ca(2+)-passing channel implicated in the sensing of forces, including those acting on bones. To date, 33 mutations are known to affect human bone development to different extents. The spectrum of these skeletal dysplasias (SD) ranges from dominantly inherited mild brachylomia (BO) to neonatal lethal forms of metatropic dysplasia (MD). Complexities of the results from fluorescence and electrophysiological studies have led to questions on whether channel activity is a good predictor of disease severity. Here we report on a systematic examination of 14 TRPV4 mutant alleles covering the entire SD spectrum. Expressed in Xenopus oocyte and without any stimulation, the wild-type channel had a ~1% open probability (Po) while those of most of the lethal MD channels approached 100%. All mutant channels had higher basal open probabilities, which limited their further increase by agonist or hypotonicity. The magnitude of this limitation revealed a clear correlation between the degree of over-activity (the molecular phenotype) and the severity of the disease over the entire spectrum (the biological phenotype). Thus, while other factors are at play, our results are consistent with the increased TRPV4 basal activity being a critical determinant of the severity of skeletal dysplasia. We discuss how the channel over-activity may lead to the "gain-of-function" phenotype and speculate that the function of wild-type TRPV4 may be secondary in normal bone development but crucial in an acute process such as fracture repair in the adult.
    PLoS ONE 05/2011; 6(5):e19533. DOI:10.1371/journal.pone.0019533 · 3.23 Impact Factor
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