A Novel Deletion Mutation in the Arginine Vasopressin Receptor 2 Gene and Skewed X Chromosome Inactivation in a Female Patient with Congenital Nephrogenic Diabetes Insipidus

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Title: A Novel Deletion Mutation in the Arginine Vasopressin Receptor 2 Gene and Skewed X Chromosome Inactivation in a Female Patient with Congenital Nephrogenic Diabetes Insipidus
Authors: Kinoshita, K.; Miura, MD, PhD, Yoshitaka; Nagasaki, H.; Murase, T.; Bando, Y.; Oiso, MD, PhD, Yutaka
Publisher: Journal of Endocrinological Investigation
Date Published: February 01, 2004
Reference Number: 651
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X-linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder caused by mutations in the arginine vasopressin receptor 2 (V2R) gene. The clinical phenotype is fully expressed in hemizygous male patients and is usually asymptomatic in heterozygous females. In the present study, a 51-yr-old Japanese female with congenital NDI and her family members were examined. The patient developed severe hypernatremia accompanied by hypoosmotic polyuria after gynecological surgery, and was unable to concentrate urinary osmolality in response to exogenous vasopressin. Direct sequencing analysis of the propositus and her two affected sons revealed a two-nucleotide deletion change at codon 30 (g.452-453delAC) in the V2R gene, resulting in a frameshift and premature termination in translation at codon 190. The X chromosome inactivation pattern was investigated in the propositus using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene, and the value for relative X chromosome inactivation of one allele was 70.2%. In conclusion, we identified a novel V2R gene mutation in a female patient and her sons with congenital NDI, and her phenotype may be caused by skewed X chromosome inactivation.

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 vasopressin 2 receptor (V2R) gene is carried on the X chromosome. Mutation of the V2R gene is responsible for NDI. The majority of cases of X-linked NDI are seen in males. This is because males have only one X chromosome, which they inherit from their mothers. Should the inherited X chromosome contain a mutated V2R gene, the male will have NDI. The female carrier of the mutated V2R has 2 X chromosomes and generally one of these X chromosomes carries a normal V2R gene that produces sufficient amounts of the V2R protein so that the female will be able to concentrate urine and not experience NDI.

Occasionally, however, females can experience congenital NDI. This generally occurs when they have a mutated V2R gene on one X chromosome non-random inactivation of the X chromosome that bears the normal V2R gene. Kinoshita, et al., report such a case. They examined a 51 year old Japanese woman and her sons. Her two sons were diagnosed with NDI at the age of 1 year and 10 days, respectively. The mother first showed signs of NDI during her pregnancy at age 25. Her symptoms were mild. She received gynecological surgery at age 51 and afterwards experienced more severe symptoms of NDI. The reason for this is unclear. However, she currently experiences mild symptoms and is being treated with occasional use of indomethacin.

The nature of her and her sons’ V2R gene mutation resulted in a V2R protein that is truncated. That is, it is missing a significant part of its normal length. This mutant V2R would most likely not be able to reach the cell membrane where it must be if it is to perform its function.