Nephrogenic Diabetes Insipidus: An X Chromosome-Linked Dominant Inheritance Pattern with a Vasopressin Type 2 Receptor Gene that is Structurally Normal
| Title: | Nephrogenic Diabetes Insipidus: An X Chromosome-Linked Dominant Inheritance Pattern with a Vasopressin Type 2 Receptor Gene that is Structurally Normal |
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| Authors: | Friedman, Eitan; Bale, Allen E.; Carson, Emma; Boson, Wolfanga L.; Nordenskjold, Magnus; Ritzen, Martin; Ferreira, Paulo C.; Jammal, Anibal; De Marco, Luiz |
| Publisher: | Proceedings of the National Academy of Sciences of the United States of America |
| Date Published: | August 30, 1994 |
| Reference Number: | 92 |
Nephrogenic diabetes insipidus is a rare hereditary disorder, most commonly transmitted in an X chromosome-linked recessive manner and characterized by the lack of renal response to the action of antidiuretic hormone [Arg8] vasopressin. The vasopressin type 2 receptor (V2R) has been suggested to be the gene that causes the disease, and its role in disease pathogenesis is supported by mutations within this gene in affected individuals. Using the PCR, denaturing gradient gel electrophoresis, and direct DNA sequencing, we examined the V2R gene in four unrelated kindreds. In addition, linkage analysis with chromosome Xq28 markers was done in one large Brazilian kindred with an apparent unusual X chromosome-linked dominant inheritance pattern. In one family, a mutation in codon 280, causing a Tyr-->Cys substitution in the sixth transmembrane domain of the receptor, was found. In the other three additional families with nephrogenic diabetes insipidus, the V2R-coding region was normal in sequence. In one large Brazilian kindred displaying an unusual X chromosome-linked dominant mode of inheritance, the disease-related gene was localized to the same region of the X chromosome as the V2R, but no mutations were found, thus raising the possibility that this disease is caused by a gene other than V2R.
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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)
Either of the pairs of genes may take any of several forms. These forms are called alleles (An allele is still a gene.). For example, the gene pair controlling the trait of eye color exists as two main alleles, one that can produce brown eyes and one that can produce blue eyes. A person can inherit two alleles for brown eyes, one from his father and one from his mother, and therefore be born with brown eyes. If an individual received one allele for brown eyes and another for blue eyes, he or she would still end up with brown eyes because the brown eye allele is dominant. That is, it only needs itself to produce brown eyes. The blue eye allele is recessive, that is, it needs both alleles to be blue eye alleles in order to produce blue eyes.
NDI can be inherited in an X-linked recessive manner. This means that when a female inherits the mutated V2R gene in a single dose, (i.e., only one of the V2R alleles is mutated) it is generally masked by the other, normal V2R allele on her other X chromosome. Thus, it is likely she will not manifest any of the symptoms of NDI. However, when a male inherits the defective V2R gene, there is no normal V2R allele (gene) on a second X chromosome to mask its effects because males have only one X chromosome. Thus, the male is likely to manifest the symptoms of NDI.
Friedman, et al., analyzed the V2R genes of four unrelated families, one of which spanned five generations. Individual members within each of these four families displayed symptoms of NDI. Further, standard tests showed that their disorder was indeed NDI. However, the authors research provided some unusual findings. The NDI inheritance pattern of the five generation family was X-linked dominant, which meant only a single mutant V2R allele would be required in order for the disorder to manifest. This was born out by this family having a higher incidence than normal of females expressing NDI. More surprisingly, in three of the four families, the researchers could find no defect in the V2R genes, though the pattern of inheritance was X-chromosome recessive. This led the authors to speculate that, in some cases, X-linked NDI may be caused by some other gene that is located somewhere near the V2R gene.