title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
abstract: 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.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Carpentier
authors.forename: Larry A
authors.initials: LA
authors.lastname: Greenbaum
authors.forename: Driss
authors.initials: D
authors.lastname: Rochdi
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019390:Arrestins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007010:Hyponatremia / Q000235:genetics; D007177:Inappropriate ADH Syndrome / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D050505:Mutant Proteins; D017483:Receptors, Vasopressin; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins