Molecular Identification of the Gene Responsible for Congenital Nephrogenic Diabetes Insipidus

Title: Molecular Identification of the Gene Responsible for Congenital Nephrogenic Diabetes Insipidus
Authors: Rosenthal, Walter; Seibold, Anita; Antaramian, Anaid; Lonergan, Michele; Arthus, Marie-Francoise; Hendy, PhD, Geoffrey N.; Birnbaumer, Mariel; Bichet, Daniel G.
Publisher: Nature
Date Published: September 17, 1992
Reference Number: 299
Antidiuretic hormone (arginine vasopressin) binds to and activates V2 receptors in renal collecting tubule cells. Subsequent stimulation of the Gs/ adenylyl cyclase system promotes insertion of water pores into the luminal membrane and thereby reabsorption of fluid. In congenital nephrogenic diabetes insipidus (CNDI), an X-linked recessive disorder, the kidney fails to respond to arginine vasopressin. Here we report that an affected male of a family with CNDI has a deletion in the open reading frame of the V2 receptor gene, causing a frame shift and premature termination of translation in the third intracellular loop of the receptor protein. A normal receptor gene was found in the patient's brother. Both the normal and the mutant allele were detected in his mother. A different mutation, causing a codon change in the third transmembrane domain of the V2 receptor, was found in the open reading frame of an affected male but not in the unaffected brother belonging to another family suffering from CNDI.

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)

Researchers have identified the molecular sequence that results in the kidney collecting ducts being able to reabsorb water passing through them, and which allows the kidney to concentrate urine. The antidiuretic hormone, arginine vasopressin (AVP) binds with the vasopressin-2 receptor (V2R) located in the principal cells of the kidney collecting duct. This stimulates the G-protein (to which the V2R is coupled) and the adenylyl cyclase system to promote insertion of water transporting proteins into the kidney duct cell membranes. This makes the cell membranes more able to reabsorb water.

In X-linked congenital NDI, the kidney is unable to respond to AVP and therefore can neither reabsorb water nor concentrate urine. Thus body water balance is upset. Rosenthal, et al., analyzed the V2R gene of two unrelated NDI patients, both males. They found a different mutation in each of the patient's V2R genes.

Both patients had brothers free from NDI. Their V2R genes were normal. The mother of each patient had one normal V2R gene and one mutated V2R gene. The V2R gene is located on the X chromosome. Males have only one X chromosome, passed on to them from their mother. Females have two X chromosomes, having received one from their mother and one from their father. Females are able to carry and pass on a mutated V2R gene but not express the disorder because their normal V2R gene creates enough normal V2Rs to do the job required of them. Thus the presence of the mutated V2R gene is masked by the normal V2R gene.

The first NDI patient had a mutation in his V2R gene that terminated the gene's protein-making process before the gene could make a complete V2R. This caused the V2Rs produced by this V2R gene to be missing their carboxy terminus, rendering it nonfunctional. (You can look at a diagram of V2R here.) The second NDI patient had a different V2R gene mutation than the first. This mutation caused a substitution of the amino acid aspartic acid for the amino acid alanine. This substitution causes a change in the structure of the V2R.

This research identifies the X-linked mode of inheritance of this form of NDI and the V2R gene as the gene, when mutated, responsible for NDI.