Clinical Phenotype of Nephrogenic Diabetes Insipidus in Females Heterozygous for a Vasopressin Type 2 Receptor Mutation

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Title: Clinical Phenotype of Nephrogenic Diabetes Insipidus in Females Heterozygous for a Vasopressin Type 2 Receptor Mutation
Authors: van Lieburg, Angenita; Verdijk, Marian A.J.; Schoute, Frans; Ligtenberg, Marjolijn J.L.; van Oost, Bernard A.; Waldhauser, Franz; Dobner, Maria; Monnens, Leo A.H.; Knoers, Nine
Publisher: Human Genetics
Date Published: July 01, 1995
Reference Number: 59
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Abstract • Translation
Nephrogenic diabetes insipidus (NDI) usually shows an X-linked recessive mode of inheritance caused by mutations in the vasopressin type 2 receptor gene (AVPR2). In the present study, three NDI families are described in which females show clinical features resembling the phenotype in males. Maximal urine osmolality in three female patients did not exceed 200 mosmol/kg and the absence of extra-renal responses to 1-desamino-8-D-arginine vasopressin was demonstrated in two of them. All affected females and two asymptomatic female family members were shown to be heterozygous for an AVPR2 mutation. Skewed X-inactivation is the most likely explanation for the clinical manifestation of NDI in female carriers of an AVPR2 mutation. It is concluded that, in female NDI patients, the possibility of heterozygosity for an AVPR2 gene mutation has to be considered in addition to homozygosity for mutations in the aquaporin-2 gene.

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)

The most common form of inherited nephrogenic diabetes insipidus (NDI) is the X-linked recessive mode of inheritance caused by mutations in the vasopressin-2 receptor (V2R) gene located on the long arm of the X chromosome. Generally, genes come in pairs - one inherited from the mother, one inherited from the father. Specific gene pairs control specific characteristics, for example, there is a gene pair that controls for eye color. Either of the gene pairs controlling a trait may take any of several forms, called alleles. For example, one of the genes in a gene pair for eye color may code for brown, the other may code for blue. Since the gene for brown is dominant over the gene for blue, (another way of saying this is blue is recessive to brown) if the offspring has inherited a gene for brown, say from his mother, and a gene for blue from his father, then the offspring will have brown eyes.

Males and females differ in their sex chromosomes; females have two X chromosomes and males have one X chromosome and one Y chromosome. If the offspring of the mother and father is a girl, it will inherit one X chromosome from the father and one from the mother. If it is a boy, it will inherit one X chromosome form the mother and none from the father, so if there are any mutated genes on the X chromosome, the boy will tend to express them because there is no gene to pair with it from the father's side to mask its effects.

In X-linked NDI, the mutated gene is carried on the X chromosome. This results, generally, in females carrying the mutated V2R gene and not expressing it outwardly because they have another V2R gene that is often not mutated. Since the mutated V2R gene is recessive, that means the non-mutated V2R gene will generally dominate it and mask its effects. However, should the female pass the mutated V2R gene on to her son, he is likely to express it outwardly because he has no other V2R gene to mask its effects because he has only one X chromosome.

However, there are females who do express the symptoms of NDI. A portion of these cases can be explained by the fact that sometimes a mutation in another gene carried on a non-sex chromosome, the aquaporin-2 (AQP2) gene, can result in NDI. It may also be that there are other, unknown genes that, if defective, result in NDI. Another possibility is that both of the V2R gene pairs on the affected female are mutated. Then there is the phenomena of skewed X-inactivation where genes on X chromosomes are inactivated in a non-random manner.

vanLieburg, et al., analyzed the inheritance pattern and DNA of three families affected by NDI where female members expressed the full symptoms of NDI. In the first family, the affected girl's AQP2 gene was free of mutations, but her V2R gene had the same mutation as her brother, who also had NDI. In the second family, the affected girl also had a mutation in her V2R gene, and her mother had the same mutations. The affected girl's AQP2 gene was normal. The affected girl in family three showed no mutation on her V2R gene, however further analysis showed that she and two other females in her family (one being the affected girl's mother) were heterozygous for a mutation in the V2R gene. That is, in each of the females one of their gene pairs of V2R carried a mutation, the other V2R gene did not.

This study showed that female carriers of a V2R gene mutation can indeed manifest all the symptoms of NDI in early childhood (as each of the three girls did). The authors conclude that the most likely cause of NDI in these females is skewed X-inactivation, resulting in the inactivation of their normal V2R gene. This allowed the full expression of their mutated V2R gene.