Inheritance of Mutations in the V2 Receptor Gene in Thirteen Families with Nephrogenic Diabetes Insipidus

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Title: Inheritance of Mutations in the V2 Receptor Gene in Thirteen Families with Nephrogenic Diabetes Insipidus
Authors: Knoers, Nine; Ouweland, Ans M.W. van den; Verdijk, Marian A.J.; Monnens, Leo A.H.; van Oost, Bernard A.
Publisher: Kidney International
Date Published: July 01, 1994
Reference Number: 98
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Congenital nephrogenic diabetes insipidus (NDI) is an X-linked recessive disease characterized by insensitivity of the distal nephron to the antidiuretic effect of arginine vasopressin. The hypothesis that the defect underlying NDI might be a dysfunctional renal vasopressin V2 receptor has recently been proven by the identification of mutations in the V2 receptor gene in NDI patients. We examined thirteen unrelated Dutch NDI families and identified thirteen distinct and unique mutations. These included nine missense mutations, two nonsense mutations and two small deletions and were found in the extracellular domains II, III and IV, the intracellular domains II and IV and in the transmembrane loops I, II, IV and V of the vasopressin type 2 receptor. In the families with multiple NDI patients the mutated gene cosegregated with the disease. Our data suggest a higher mutation frequency in male than in female gametes. No discrepancies between carrier detection by means of DNA analysis with closely linked polymorphic markers and the definite diagnosis based on sequencing data were found.

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)

Knoers et al. wrote this article in an effort to better understand the genetic mutations that cause NDI. Like most scientific research, this study was inspired by the work of previous researchers. In this case, Knoers, et al., knew from the work of other scientists several important facts about NDI, namely;
  1. The general location of the X chromosome of the mutated gene that causes NDI, and
  2. that the NDI gene was in fact the gene for the vasopressin receptor.
In essence, Knoers, et al., began their research knowing not only the exact location of the genetic defects that cause NDI, but why these defects caused NDI. The reason is that the kidneys are unresponsive to vasopressin, a hormone needed to control the concentration of urine. The situation is analogous to a lock and key. In this case, the vasopressin hormone works like a key ready to "lock up" the kidney when necessary so that water resorption can take place. However, the genetic blueprint (DNA) that tells the kidney how to build "locks" (or "receptors") that will fit the vasopressin "key" are faulty. The kidney is unable to build the locks, so no matter how many vasopressin keys are around to tell the kidney to begin water resorption, the kidney cannot respond.

Knoers, et al., began their research understanding this important relationship. They knew that NDI was caused by faulty genetic blueprints for the vasopressin receptor, and they knew in general where in the DNA to look for these faulty blueprints. Their goal was to understand more specifically in what way the DNA blueprints were faulty. To do this, they took the DNA from thirteen NDI families in the Netherlands and analyzed it. They found that overall there were thirteen distinct mutations (or genetic mistakes) that caused NDI. The mutations differed from family to family. However, in families with several NDI patients, the mutations were the same, indicating that those family members had all inherited the same faulty genetic blueprints. The genetic analysis also allowed the researchers to determine the carrier status of females in the family (i.e., whether or not the unaffected women in the families were carrying the NDI mutations).

Using family pedigrees and the results of their genetic analysis, Knoers et al. were able to determine the origin of these mutations. In seven families, NDI was due to a new mutation, six of which came from the maternal (great)grandparents and one of which could not be determined. In the remaining families, the "mistake" was made during the formation of sperm of the maternal grandfather (3 families) and the maternal great-grandfather (1 family), and in one case during egg formation from the maternal grandmother (1 family). In one family, it was impossible to tell the origin of the mutation.

Knoers et al. finally determined the specific nature of the genetic mutations. In two cases, it was caused by a deletion (part of the genetic code was deleted by mistake), while in two others it was caused by a "nonsense" mutation (the genetic code did not "spell out" the instructions correctly). The remaining mutations were missense mutations (the DNA was not read correctly). The data suggests that mutations such as these are more common in males than in females.