title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
abstract: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently discovered rare disease caused by gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2. To date, mutations of Phe229 and Arg137 have been identified as gain-of-function in the V2 vasopressin receptor (V2R). These receptor mutations lead to hyponatremia, which may lead to clinical symptoms in infants. Here we present a newly identified I130N substitution in exon 2 of the V2R gene in a family, causing NSIAD. This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells. This basal activity could be blocked by the inverse agonist tolvaptan and arginine-vasopressin stimulation enhanced the cAMP production of I130N-V2R. The mutation causes a biased receptor conformation as the basal cAMP generation activity of I130N does not lead to interaction with β-arrestin. The constitutive activity of the mutant receptor caused constitutive dynamin-dependent and β-arrestin-independent internalization. The inhibition of basal internalization using dominant-negative dynamin resulted in an increased cell surface expression. In contrast to the constitutive internalization, agonist-induced endocytosis was β-arrestin dependent. Thus, tolvaptan could be used for treatment of hyponatremia in patients with NSIAD who carry the I130N-V2R mutation.
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.|MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: László S
authors.initials: LS
authors.lastname: Erdélyi
authors.affiliation: Endokrinologikum Frankfurt a. Main, Frankfurt, Germany.
authors.forename: W Alexander
authors.initials: WA
authors.lastname: Mann
authors.affiliation: Genomic Medicine, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Morris-Rosendahl
authors.affiliation: Molecular Diagnostics, Genteq GmbH, Hamburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Groß
authors.affiliation: Center for Nephrology and Metabolism, Weißwasser, Germany.
authors.forename: Mato
authors.initials: M
authors.lastname: Nagel
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.|MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Várnai
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.|MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Balla
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.|MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Hunyady
mesh_terms: D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry; D000242:Cyclic AMP / Q000096:biosynthesis*; D004252:DNA Mutational Analysis; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005091:Exons; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007010:Hyponatremia / Q000188:drug therapy / Q000235:genetics*; D007177:Inappropriate ADH Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D017483:Receptors, Vasopressin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000077602:Tolvaptan; D000071557:beta-Arrestins
chemical_list: C585768:AVPR2 protein, human; D065092:Antidiuretic Hormone Receptor Antagonists; D019390:Arrestins; D001552:Benzazepines; D017483:Receptors, Vasopressin; D000071557:beta-Arrestins; D000077602:Tolvaptan; D000242:Cyclic AMP; D034281:Dynamins