Brief Report: A Mutation in the Vasopressin V2-Receptor Gene in a Kindred with X-Linked Nephrogenic Diabetes Insipidus
| Title: | Brief Report: A Mutation in the Vasopressin V2-Receptor Gene in a Kindred with X-Linked Nephrogenic Diabetes Insipidus |
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| Authors: | Merendino, Jr., John J.; Spiegel, M.D., Allen M.; Crawford, M.D., John D.; O'Carroll, Anne-Marie; Brownstein, Michael J.; Lolait, Stephen J. |
| Publisher: | New England Journal of Medicine |
| Date Published: | May 27, 1993 |
| Reference Number: | 134 |
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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)
The reason the kidneys do not respond to AVP (and therefore cannot concentrate urine) is because the vasopressin V2 receptor will not bind with AVP as it does normally. It cannot do so because a mutation of the gene that synthesizes it, the V2 receptor gene, results in an improperly structured V2 receptor.
In this study, Merendino, et al., report on a mutation of the V2 receptor gene in the members of a family who have NDI.
The subject was a male of Lithuanian descent who was referred at 13 months due to his excessive thirst and excessive, dilute urine. The subject was, at the time of referral, suffering from bouts of dehydration and high sodium levels in the blood. He did not respond to synthetic AVP and was diagnosed with NDI. Later his mother gave birth to fraternal twins, one of whom also had NDI. The researchers analyzed the family's DNA, focusing on the V2 receptor gene. They found the affected males had the same V2 receptor gene mutation. The type of mutation they had is called a frameshift mutation. This type of mutation causes the gene to build its protein with a different set of amino acids than normal and this resulted in the affected male's V2 receptors being cut short, eliminating an important stretch of the genetic sequence it was supposed to carry. This missing part of the genetic sequence is essential for proper signaling within the receptor and its loss renders the V2 receptor inactive and thereby unable to respond to AVP.
Males with X-linked NDI vary in the degree to which they can respond to AVP. This is probably due to the many ways the V2 receptor gene can be mutated. That is, some mutations may leave the V2 receptor more functional than others. Mutations in the V2 receptor gene have been identified as causing NDI, and this bears clinical importance both diagnostically (a newborn male in a family known to carry a defective V2 receptor gene can be diagnosed at birth for NDI) and therapeutically (it may be possible to functionally restore V2 receptor genes through genetic therapy).