Background:AVPR2 mutations cause most cases of nephrogenic diabetes insipidus (NDI); 211 AVPR2 mutations have been described, but only 7 are described causing partial NDI. Methods: Two unrelated Thai boys had polyuria and polydipsia in infancy but had normal electrolytes and serum osmolality at 2 years of age. Patient 1 could not concentrate his urine in response to water deprivation or 1-desamino-8-D-arginine vasopressin (DDAVP); patient 2 could concentrate to ∼600 mosm/l. The patients’ AVPR2 genes were sequenced and the identified mutations were re-created in AVPR2 cDNA expression vectors. AVPR2 activities were measured by stimulating transfected HEK293T cells with arginine vasopressin (AVP) or DDAVP, and assessing the resulting cAMP production by the activation of a luciferase reporter. Results: Patient 1 carried the previously described missense mutation R181C; patient 2 carried the novel missense mutation M311V. When transiently transfected into HEK293T cells, 6.8 × 10–12M AVP induced the half-maximal response (EC50) of the wild-type, whereas the EC50 value for R181C was 5.9 × 10–9M and for M311V was 2.6 × 10–10M. Responses to DDAVP were qualitatively similar but required 10-fold higher concentrations. Conclusion: The novel AVPR2 mutation M311V retains partial activity and results in a milder form of NDI.

van Lieburg AF, Knoers NV, Monnens LA: Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1999;10:1958–1964.
Morello JP, Bichet DG: Nephrogenic diabetes insipidus. Annu Rev Physiol 2001;63:607–630.
Birnbaumer M, Seibold A, Gilbert S, Ishido M, Barberis C, Antaramian A, Brabet P, Rosenthal W: Molecular cloning of the receptor for human antidiuretic hormone. Nature 1992;357:333–335.
Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S: Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature 1993;361:549–552.
Robben JH, Knoers NV, Deen PM: Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 2006;291:F257–F270.
Spanakis E, Milord E, Gragnoli C: AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. J Cell Physiol 2008;217:605–617.
Sadeghi H, Robertson GL, Bichet DG, Innamorati G, Birnbaumer M: Biochemical basis of partial nephrogenic diabetes insipidus phenotypes. Mol Endocrinol 1997;11:1806–1813.
Ala Y, Morin D, Mouillac B, Sabatier N, Vargas R, Cotte N, Dechaux M, Antignac C, Arthus MF, Lonergan M, Turner MS, Balestre MN, Alonso G, Hibert M, Barberis C, Hendy GN, Bichet DG, Jard S: Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol 1998;9:1861–1872.
Vargas-Poussou R, Forestier L, Dautzenberg MD, Niaudet P, Dechaux M, Antignac C: Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1997;8:1855–1862.
Pasel K, Schulz A, Timmermann K, Linnemann K, Hoeltzenbein M, Jaaskelainen J, Gruters A, Filler G, Schoneberg T: Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. J Clin Endocrinol Metab 2000;85:1703–1710.
Inaba S, Hatakeyama H, Taniguchi N, Miyamori I: The property of a novel V2 receptor mutant in a patient with nephrogenic diabetes insipidus. J Clin Endocrinol Metab 2001;86:381–385.
Chen CH, Chen WY, Liu HL, Liu TT, Tsou AP, Lin CY, Chao T, Qi Y, Hsiao KJ: Identification of mutations in the arginine vasopressin receptor 2 gene causing nephrogenic diabetes insipidus in Chinese patients. J Hum Genet 2002;47:66–73.
Faerch M, Christensen JH, Corydon TJ, Kamperis K, de Zegher F, Gregersen N, Robertson GL, Rittig S: Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene. Clin Endocrinol (Oxf) 2008;68:395–403.
Robben JH, Knoers NV, Deen PM: Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model. Am J Physiol Renal Physiol 2005;289:F265–F272.
Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE: Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005;352:1884–1890.
Ranadive SA, Ersoy B, Favre H, Cheung CC, Rosenthal SM, Miller WL, Vaisse C: Identification, characterization and rescue of a novel vasopressin-2 receptor mutation causing nephrogenic diabetes insipidus. Clin Endocrinol (Oxf) 2009;71:388–393.
Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P: Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000;106:253–262.
Mouillac B, Chini B, Balestre MN, Elands J, Trumpp-Kallmeyer S, Hoflack J, Hibert M, Jard S, Barberis C: The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J Biol Chem 1995;270:25771–25777.
Derick S, Pena A, Durroux T, Wagnon J, Serradeil-Le Gal C, Hibert M, Rognan D, Guillon G: Key amino acids located within the transmembrane domains 5 and 7 account for the pharmacological specificity of the human V1b vasopressin receptor. Mol Endocrinol 2004;18:2777–2789.
Rodrigo J, Pena A, Murat B, Trueba M, Durroux T, Guillon G, Rognan D: Mapping the binding site of arginine vasopressin to V1a and V1b vasopressin receptors. Mol Endocrinol 2007;21:512–523.
Saito M, Tahara A, Sugimoto T: 1-Desamino-8-D-arginine vasopressin (dDAVP) as an agonist on V1b vasopressin receptor. Biochem Pharmacol 1997;53:1711–1717.
Del Tredici AL, Vanover KE, Knapp AE, Bertozzi SM, Nash NR, Burstein ES, Lameh J, Currier EA, Davis RE, Brann MR, Mohell N, Olsson R, Piu F: Identification of novel selective V2 receptor non-peptide agonists. Biochem Pharmacol 2008;76:1134–1141.
Albertazzi E, Zanchetta D, Barbier P, Faranda S, Frattini A, Vezzoni P, Procaccio M, Bettinelli A, Guzzi F, Parenti M, Chini B: Nephrogenic diabetes insipidus: Functional analysis of new AVPR2 mutations identified in Italian families. J Am Soc Nephrol 2000;11:1033–1043.
Pan Y, Wilson P, Gitschier J: The effect of eight V2 vasopressin receptor mutations on stimulation of adenylyl cyclase and binding to vasopressin. J Biol Chem 1994;269:31933–31937.
Fujiwara TM, Morgan K, Bichet DG: Molecular biology of diabetes insipidus. Annu Rev Med 1995;46:331–343.
Schulz A, Grosse R, Schultz G, Gudermann T, Schoneberg T: Structural implication for receptor oligomerization from functional reconstitution studies of mutant V2 vasopressin receptors. J Biol Chem 2000;275:2381–2389.
Labrou NE, Bhogal N, Hurrell CR, Findlay JB: Interaction of Met297 in the seventh transmembrane segment of the tachykinin NK2 receptor with neurokinin A. J Biol Chem 2001;276:37944–37949.
Bouley R, Pastor-Soler N, Cohen O, McLaughlin M, Breton S, Brown D: Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (viagra). Am J Physiol Renal Physiol 2005;288:F1103–F1112.
Robben JH, Sze M, Knoers NV, Deen PM: Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 2007;292:F253–F260.
Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, Bouvier M: Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 2000;105:887–895.
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