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Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD

Carpentier, Eric and Greenbaum, Larry A. and Rochdi, Driss and Abrol, Ravinder and Goddard, William A., III and Bichet, Daniel G. and Bouvier, Michel (2012) Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD. Journal of the American Society of Nephrology, 23 (10). pp. 1635-1640. ISSN 1046-6673. PMCID PMC3458462. doi:10.1681/ASN.2012010077.

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Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.

Item Type:Article
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URLURL TypeDescription CentralArticle
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2012 by the American Society of Nephrology. Received for publication January 24, 2012. Accepted for publication July 6, 2012. Published online before print September 6, 2012. E.C. and L.A.G. contributed equally to this work. We are grateful to Dr. Serradeil-Le-Gal from Sanofi-Aventis for kindly providing satavaptan (SR121463) and Drs. Komuro and Czerwiec from Otsuka Pharmaceutical for their generous gift of tolvaptan (OPC41061). We also thank Christian Charbonneau for his expertise and help in confocal microscopy and Dr. Monique Lagacé for her critical reading of the manuscript. This work was supported by grants from the Kidney Foundation of Canada and the Canadian Institutes of Health Research to M. B. E.C was supported by a doctoral studentship from the Fond de la Recherche en Santé du Québec. M.B. holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology.
Funding AgencyGrant Number
Kidney Foundation of CanadaUNSPECIFIED
Canadian Institutes of Health ResearchUNSPECIFIED
Fond de la Recherche en Santé du QuébecUNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC3458462
Record Number:CaltechAUTHORS:20121204-143945341
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Official Citation:Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD Eric Carpentier, Larry A. Greenbaum, Driss Rochdi, Ravinder Abrol, William A. Goddard III, Daniel G. Bichet, and Michel Bouvier JASN September 28, 2012 23: 1635-1640; published ahead of print September 6, 2012, doi:10.1681/ASN.2012010077
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35799
Deposited By: Ruth Sustaita
Deposited On:04 Dec 2012 23:12
Last Modified:09 Nov 2021 23:17

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