Mutations in the Vasopressin Type 2 Receptor Gene (AVPR2) Associated with Nephrogenic Diabetes Insipidus

Title: Mutations in the Vasopressin Type 2 Receptor Gene (AVPR2) Associated with Nephrogenic Diabetes Insipidus
Authors: Verdijk, Marian A.J.; van Oost, Bernard A.; Monnens, Leo A.H.; Knoers, Nine; Dreesen, Jos C.F.M.; Rocchi, Mariano; Ouweland, Ans M.W. van den
Publisher: Nature Genetics
Date Published: October 01, 1992
Reference Number: 254
Nephrogenic diabetes insipidus (DIR) is an X-linked disorder characterized by insensitivity of the distal nephron for the pituitary hormone, vasopressin. The genetic map location of the DIR gene on chromosome Xq28 coincides with the physical map location of the functional vasopressin renal V2-type receptor. Recently, the human and rat cDNAs for the vasopressin V2 receptor (AVPR2) have been identified. We show here that the structural AVPR2 gene is localized between DXS52 and G6PD, which is within the genetic map location of DIR. We also tested eight X-linked DIR probands and their families for mutations in one of the most conserved extracellular regions of AVPR2: in three of them, we have identified point mutations resulting in non-conservative amino acid substitutions which cosegregated with DIR in all families.

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)

Congenital X-linked nephrogenic diabetes insipidus (NDI) is most commonly an X-linked disorder, which means the gene responsible for this form of NDI is located somewhere on the X chromosome. NDI is characterized by the kidney's inability to respond to the antidiuretic hormone, arginine vasopressin (AVP). The result of this is that the kidneys are not able to maintain body water balance by concentrating urine and reabsorbing the water passing through the kidney collecting ducts.

Geneticists have mapped the location of the gene they believe is, when mutated, responsible for NDI to the X28 region of the X-chromosome. The vasopressin-2 receptor (V2R) gene is located in the same area. V2Rs manufactured by the V2R gene play an important role in the kidney water reabsorption and urine concentrating process so researchers proposed that the gene responsible for NDI may, in fact, be the V2R gene.

The research of van den Ouweland, et al., affirmed that the V2R gene is located within the same region as the NDI-causing gene. They also provided strong evidence that the V2R gene is the NDI-causing gene by testing eight NDI patients and their families for mutations in a small but functionally important part of the V2R, the third extracellular loop. (You can look at a diagram of V2R here.)

In three of the NDI patients, the researchers found point mutations, all resulting in the substitution of the amino acid cysteine for the amino acid that should normally be present (a glycine in patient 128 and a tyrosine in patient 134, and an arginine in patient 350). This direct mutational analysis has substantiated that the V2R gene is identical with the NDI gene. In other words, mutations in the V2R gene are responsible for congenital X-linked NDI.