Vasopressin Type 2 Receptor V88M Mutation: Molecular Basis of Partial and Complete Nephrogenic Diabetes Insipidus

被引:34
作者
Bockenhauer, Detlef [1 ]
Carpentier, Eric [2 ,3 ]
Rochdi, Driss [2 ,3 ]
van't Hoff, W. [1 ]
Breton, Billy [2 ,3 ]
Bernier, Virginie [2 ,3 ]
Bouvier, Michel [2 ,3 ]
Bichet, Daniel G. [4 ,5 ,6 ]
机构
[1] Great Ormond St Hosp Sick Children, London WC1N 3JH, England
[2] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada
[3] Univ Montreal, Grp Rech Univ Medicament, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada
[4] Univ Montreal, Dept Med & Physiol, Montreal, PQ H3C 3J7, Canada
[5] Hop Sacre Coeur, Unite Rech Clin, Ctr Rech, Montreal, PQ H4J 1C5, Canada
[6] Hop Sacre Coeur, Serv Nephrol, Montreal, PQ H4J 1C5, Canada
来源
NEPHRON PHYSIOLOGY | 2010年 / 114卷 / 01期
关键词
CELL-SURFACE EXPRESSION; PHARMACOLOGICAL CHARACTERIZATION; AVPR2; MUTATIONS; CHAPERONES; MUTANTS; RESCUE;
D O I
10.1159/000245059
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background/Aims: Mutations in the type 2 vasopressin receptor gene (AVPR2) underlie X-linked recessive nephrogenic diabetes insipidus (NDI). Here, we report on a family with a mutation in AVPR2, c.262G>A (p.V88M). This recurrently identified mutation was previously shown to abolish AVPR2 function, yet in some affected members, urine osmolalities of up to 570 mosm/kg were observed. We detail the variable clinical phenotype and investigate its molecular basis. Methods: Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors. Results: Clinical data were available on 6 patients. Four of these demonstrated a substantial increase in urinary concentration after 1-desamino[8-D-arginine] vasopressin, consistent with partial NDI, while 2 did not respond. In vitro analysis revealed a reduced cell surface expression and decreased binding affinity for arginine-vasopressin of the mutant receptor, leading to blunted signaling activity. Treatment with the pharmacological chaperone SR121463 enhanced cell surface expression. Conclusion: The V88M mutation is associated with phenotypical diversity, which may be explained by the fact that both the expression level and the hormone-binding affinity are affected by the mutation. Our results provide a rational basis for treatment trials with vasopressin analogues in combination with pharmacologic chaperones in patients with this recurrently identified mutation. Copyright (C) 2009 S. Karger AG, Basel
引用
收藏
页码:1 / 10
页数:10
相关论文
共 21 条
[1]  
Ala Y, 1998, J AM SOC NEPHROL, V9, P1861
[2]  
Arthus MF, 2000, J AM SOC NEPHROL, V11, P1044, DOI 10.1681/ASN.V1161044
[3]   Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor [J].
Barak, Larry S. ;
Salahpour, Ali ;
Zhang, Xiaodong ;
Masri, Bernard ;
Sotnikova, Tatyana D. ;
Ramsey, Amy J. ;
Violin, Jonathan D. ;
Lefkowitz, Robert J. ;
Caron, Marc G. ;
Gainetdinov, Raul R. .
MOLECULAR PHARMACOLOGY, 2008, 74 (03) :585-594
[4]   Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059 [J].
Bernier, V ;
Lagacé, M ;
Lonergan, M ;
Arthus, MF ;
Bichet, DG ;
Bouvier, M .
MOLECULAR ENDOCRINOLOGY, 2004, 18 (08) :2074-2084
[5]   Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus [J].
Bernier, Virginie ;
Morello, Jean-Pierre ;
Zarruk, Alexandro ;
Debrand, Nicolas ;
Salahpour, Ali ;
Lonergan, Michle ;
Arthus, Marie-Francoise ;
Laperriere, Andre ;
Brouard, Remi ;
Bouvier, Michel ;
Bichet, Daniel G. .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2006, 17 (01) :232-243
[6]  
BICHET DG, 1994, AM J HUM GENET, V55, P278
[7]   AN EXTRACELLULAR CONGENITAL NEPHROGENIC DIABETES-INSIPIDUS MUTATION OF THE VASOPRESSIN RECEPTOR REDUCES CELL-SURFACE EXPRESSION, AFFINITY FOR LIGAND, AND COUPLING TO THE G(S)/ADENYLYL CYCLASE SYSTEM [J].
BIRNBAUMER, M ;
GILBERT, S ;
ROSENTHAL, W .
MOLECULAR ENDOCRINOLOGY, 1994, 8 (07) :886-894
[8]   Antenatal Bartters syndrome: why is this not a lethal condition [J].
Bockenhauer, D. ;
Cruwys, M. ;
Kleta, R. ;
Halperin, L. F. ;
Wildgoose, P. ;
Souma, T. ;
Nukiwa, N. ;
Cheema-Dhadli, S. ;
Chong, C. K. ;
Kamel, K. S. ;
Davids, M. R. ;
Halperin, M. L. .
QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, 2008, 101 (12) :927-942
[9]  
Bockenhauer D., 2008, Comprehensive Pediatric Nephrology, P489
[10]   Development of water transport in the collecting duct [J].
Bonilla-Felix, M .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2004, 287 (06) :F1093-F1101