A Low-Affinity Vasopressin V2-Receptor Gene in a Kindred with X-Linked Nephrogenic Diabetes Insipidus

Title: A Low-Affinity Vasopressin V2-Receptor Gene in a Kindred with X-Linked Nephrogenic Diabetes Insipidus
Authors: Yokoyama, Kenji; Yamauchi, MD, Atsushi; Izumi, Masaaki; Itoh, Takahito; Ando, Akio; Imai, Enyu; Kamada, Takenobu; Ueda, Naohiko
Publisher: Journal of the American Society of Nephrology
Date Published: March 01, 1996
Reference Number: 30
In this study, a mutation in vasopressin Type 2 receptor (V2R) in a patient with hereditary nephrogenic diabetes insipidus (NDI) has been identified and characterized. The sequencing of the V2R gene from the patient revealed that there was a missense mutation (TAT to TGT) resulting in the substitution of 205Tyr for Cys in the putative third extracellular domain. The expression analysis in CPS cells showed that the binding affinity of the mutant receptor (KD - 19.8 nM) for arginine vasopressin was much lower than that of the wild-type receptor (KD - 1.8 nM) so that intracellular cAMP production stimulated by arginine vasopressin was impaired in cells with the mutant V2R. From these results, it was concluded that the single amino-acid substitution of V2R is responsible for this familial disease.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

In hereditary nephrogenic diabetes insipidus (NDI), the kidneys do not respond to the message of the antidiuretic hormone, arginine vasopressin (AVP). This results in the inability of the kidneys to concentrate urine. Normally, AVP will bind with a special receptor called a Type 2 vasopressin receptor (V2R) that is itself already coupled to the enzyme adenylyl cyclase by means of a GTP binding protein. When the AVP binds with the V2R, it activates adenylyl cyclase which, in turn, generates cAMP which, in turn, activates protein kinase A. This initiates a metabolic process called phosphorylation which introduces a phosphate group into molecules. This increases water permeability of the kidneys' collecting duct cells by shuttling water-transporting proteins called aquaporins into the cell membranes. And all this allows the kidneys to concentrate urine.

In the past few years, the genetic basis of hereditary NDI has been established, linking it to mutations in either the V2R gene or the aquaporin-2 (AQP2) gene. Geneticists know what normal V2R genes and AQP2 genes look like, and they have identified a number of different types of mutations in them that result in NDI. Yokoyama, et al., report on the V2R gene mutation of a 46-year-old Japanese male with inherited NDI. His was a missense mutation, a kind of mutation that causes a single amino acid change in the genetic sequence of the gene. In this case, the amino acid 205 Tyr was in the place where Cys was supposed to be. This single amino acid change was located in a part of the V2R gene called the second extracellular loop, which is considered important for hormone binding. Laboratory tests of the mutated V2R revealed it could not bind AVP and this, in turn, inhibited cAMP production.

Speculating about the structure-function relationship of V2R, the authors noted that data on other receptors with similar structures reveal that the first and second extracellular loops are considered to form the three-dimensional structure to which AVP may bind. Since the V2R mutation they studied was in the second extracellular loop, causing a change in the structure of the loop, it is likely that the altered structure was unsuitable for AVP so it could not bind with the receptor and transfer the hormonal message which begins the urine concentrating sequence.