Vasopressin Receptor Mutations in Nephrogenic Diabetes Insipidus

  • Daniel G. Bichet
    Address reprint requests to Daniel G. Bichet, MD, Research Centre, Hôpital du Sacré-Coeur de Montréal, 5400 Boulevard Gouin West, Montréal, Québec H4J 1C5, Canada.
    Genetics of Renal Diseases, Groupe d'Étude des Protéines, Membranaires, Montréal, Québec, Canada. Department of Medicine and Physiology, Université de Montréal, Research Centre, Montréal, Québec, Canada. Nephrology Service, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada.
    Search for articles by this author


      The purpose of this review is first to describe the importance of early detection of vasopressin receptor mutations responsible for X-linked nephrogenic diabetes insipidus (NDI). We have proposed that all families with hereditary diabetes insipidus should have their molecular defect identified because early diagnosis and treatment of affected infants can avert the physical and mental retardation that results from repeated episodes of dehydration. Secondly, 95 published missense mutations responsible for X-linked NDI are likely to result in misfolded arginine-vasopressin V2 receptors that are trapped in the endoplasmic reticulum. These misfolded receptors are unable to reach the plasma membrane in principal collecting duct cells and to engage the circulating antidiuretic hormone, arginine-vasopressin. These misfolded proteins potentially could be rescued with pharmacologic chaperones, an active area of research pertinent to other hereditary protein misfolding diseases such as cystic fibrosis, phenylketonuria, and Anderson-Fabry disease among many others. Finally, a long-term careful surveillance of all patients with hereditary NDI should be performed to prevent chronic renal failure likely caused by the long-term functional tract obstruction with reflux.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Seminars in Nephrology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Fredriksson R.
        • Lagerstrom M.C.
        • Lundin L.G.
        • Schioth H.B.
        The G-protein-coupled receptors in the human genome form five main families.
        Mol Pharmacol. 2003; 63: 1256-1272
        • Perez D.M.
        The evolutionarily triumphant G-protein-coupled receptor.
        Mol Pharmacol. 2003; 63: 1202-1205
        • Rasmussen S.G.
        • Choi H.J.
        • Rosenbaum D.M.
        • Kobilka T.S.
        • Thian F.S.
        • Edwards P.C.
        • et al.
        Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.
        Nature. 2007; 450: 383-387
        • Cherezov V.
        • Rosenbaum D.M.
        • Hanson M.A.
        • Rasmussen S.G.
        • Thian F.S.
        • Kobilka T.S.
        • et al.
        High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.
        Science. 2007; 318: 1258-1265
        • Rosenbaum D.M.
        • Cherezov V.
        • Hanson M.A.
        • Rasmussen S.G.
        • Thian F.S.
        • Kobilka T.S.
        • et al.
        GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function.
        Science. 2007; 318: 1266-1273
        • Nielsen S.
        • Frokiaer J.
        • Marples D.
        • Kwon T.H.
        • Agre P.
        • Knepper M.A.
        Aquaporins in the kidney: from molecules to medicine.
        Physiol Rev. 2002; 82: 205-244
        • Tasken K.
        • Aandahl E.M.
        Localized effects of cAMP mediated by distinct routes of protein kinase A.
        Physiol Rev. 2004; 84: 137-167
        • McConnachie G.
        • Langeberg L.K.
        • Scott J.D.
        AKAP signaling complexes: getting to the heart of the matter.
        Trends Mol Med. 2006; 12: 317-323
        • Zaccolo M.
        • Pozzan T.
        Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes.
        Science. 2002; 295: 1711-1715
        • Henn V.
        • Edemir B.
        • Stefan E.
        • Wiesner B.
        • Lorenz D.
        • Theilig F.
        • et al.
        Identification of a novel A-kinase anchoring protein 18 isoform and evidence for its role in the vasopressin-induced aquaporin-2 shuttle in renal principal cells.
        J Biol Chem. 2004; 279: 26654-26665
        • Chen L.
        • Marquardt M.L.
        • Tester D.J.
        • Sampson K.J.
        • Ackerman M.J.
        • Kass R.S.
        Mutation of an A-kinase-anchoring protein causes long-QT syndrome.
        Proc Natl Acad Sci U S A. 2007; 104: 20990-20995
        • Yang B.
        • Bankir L.
        • Gillespie A.
        • Epstein C.J.
        • Verkman A.S.
        Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B.
        J Biol Chem. 2002; 277: 10633-10637
        • Yang B.
        • Bankir L.
        Urea and urine concentrating ability: new insights from studies in mice.
        Am J Physiol Renal Physiol. 2005; 288: F881-F896
        • Bankir L.
        • Fernandes S.
        • Bardoux P.
        • Bouby N.
        • Bichet D.G.
        Vasopressin-V2 receptor stimulation reduces sodium excretion in healthy humans.
        J Am Soc Nephrol. 2005; 16: 1920-1928
        • Snyder P.M.
        Minireview: regulation of epithelial Na+ channel trafficking.
        Endocrinology. 2005; 146: 5079-5085
        • Fujiwara T.M.
        • Bichet D.G.
        Molecular biology of hereditary diabetes insipidus.
        J Am Soc Nephrol. 2005; 16: 2836-2846
        • Arthus M.F.
        • Lonergan M.
        • Crumley M.J.
        • Naumova A.K.
        • Morin D.
        • De Marco L.A.
        • et al.
        Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus.
        J Am Soc Nephrol. 2000; 11: 1044-1054
        • Morello J.P.
        • Salahpour A.
        • Laperrière A.
        • Bernier V.
        • Arthus M.-F.
        • Lonergan M.
        • et al.
        Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants.
        J Clin Invest. 2000; 105: 887-895
        • Conn P.M.
        • Ulloa-Aguirre A.
        • Ito J.
        • Janovick J.A.
        G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo.
        Pharmacol Rev. 2007; 59: 225-250
        • Romisch K.
        A cure for traffic jams: small molecule chaperones in the endoplasmic reticulum.
        Traffic. 2004; 5: 815-820
        • Cravatt B.F.
        • Simon G.M.
        • Yates 3rd, J.R.
        The biological impact of mass-spectrometry-based proteomics.
        Nature. 2007; 450: 991-1000
        • Wang X.
        • Venable J.
        • LaPointe P.
        • Hutt D.M.
        • Koulov A.V.
        • Coppinger J.
        • et al.
        Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.
        Cell. 2006; 127: 803-815
        • Cohen F.E.
        • Kelly J.W.
        Therapeutic approaches to protein-misfolding diseases.
        Nature. 2003; 426: 905-909
        • Bernier V.
        • Morello J.P.
        • Zarruk A.
        • Debrand N.
        • Salahpour A.
        • Lonergan M.
        • et al.
        Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus.
        J Am Soc Nephrol. 2006; 17: 232-243
        • Bernier V.
        • Lagace M.
        • Lonergan M.
        • Arthus M.F.
        • Bichet D.G.
        • Bouvier M.
        Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059.
        Mol Endocrinol. 2004; 18: 2074-2084
        • Ulinski T.
        • Grapin C.
        • Forin V.
        • Vargas-Poussou R.
        • Deschenes G.
        • Bensman A.
        Severe bladder dysfunction in a family with ADH receptor gene mutation responsible for X-linked nephrogenic diabetes insipidus.
        Nephrol Dial Transplant. 2004; 19: 2928-2929
        • Shalev H.
        • Romanovsky I.
        • Knoers N.V.
        • Lupa S.
        • Landau D.
        Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus.
        Nephrol Dial Transplant. 2004; 19: 608-613
        • Yang B.
        • Zhao D.
        • Qian L.
        • Verkman A.S.
        Mouse model of inducible nephrogenic diabetes insipidus produced by floxed aquaporin-2 gene deletion.
        Am J Physiol Renal Physiol. 2006; 291: F465-F472
        • Tesmer J.J.
        • Sunahara R.K.
        • Gilman A.G.
        • Sprang S.R.
        Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS.
        Science. 1997; 278: 1907-1916
        • Mouillac B.
        • Chini B.
        • Balestre M.N.
        • Elands J.
        • Trumpp-Kallmeyer S.
        • Hoflack J.
        • et al.
        The binding site of neuropeptide vasopressin V1a receptor.
        J Biol Chem. 1995; 270: 25771-25777