Brief Report: A Molecular Defect in the Vasopressin V2-Receptor Gene Causing Nephrogenic Diabetes Insipidus
| Title: | Brief Report: A Molecular Defect in the Vasopressin V2-Receptor Gene Causing Nephrogenic Diabetes Insipidus |
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| Authors: | Holtzman, M.D., Eliezer J.; Harris, H. William; Botelho, MD, Barbara; Ausiello, M.D., Dennis A.; Guay-Woodford, MD, Lisa M.; Kolakowski, PhD, Lee F. |
| Publisher: | New England Journal of Medicine |
| Date Published: | May 27, 1993 |
| Reference Number: | 133 |
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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)
Congenital nephrogenic diabetes insipidus (NDI) is a rare disorder that occurs when the kidneys do not respond to AVP. The result is polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst). NDI can manifest in the first weeks of life and then the symptoms also include severe dehydration and high blood sodium. This can lead to physical and mental retardation, and even death if the NDI goes undiagnosed and untreated. The most common form of congenital NDI is inherited in an X-linked pattern, which means that females can carry the trait and not express its symptoms fully, and they can pass it on to their sons who will express the disorder's symptoms.
Research determined that the gene responsible for X-linked NDI is carried on the long arm of the X chromosome in region 28, which is where the V2R gene is also located. Holtzman, et al., studied 40 members of a large Ulster Scot family located in Maine. This extended family had a high incidence of NDI and were descendants of the original Scottish family that some researchers proposed were the source of all or most cases of NDI in North America.
The authors analyzed the V2R gene of those in the family who either had NDI or, as determined by the inheritance pattern, carried the NDI-causing gene. Then they compared it with the V2R gene of those in the family who neither had nor carried NDI. They discovered that those with NDI all had the same mutation of their V2R gene.
Every gene is composed of a unique sequence of the nucleotide bases adenine (A), cytosine (C), guanine (G) and thymine (T). Each set of three of these nucleotides, called a codon, (e.g. CGG, TGG, GGG, CCA) forms a single amino acid in the protein the gene synthesizes. If one of the nucleotides is out of sequence or one nucleotide is in a spot another nucleotide is supposed to be, then this alters the amino acid that goes into the protein the gene synthesizes. This alters the protein's structure, and this can affect its ability to function.
In this mutation, a thymine was where a cytosine was supposed to be. This resulted in the tryptophan amino acid being where an argine amino acid was supposed to be in the V2R. Though the authors did not carry out studies to see how this structural alteration in the V2R affected its ability to carry out its function, they speculated that it caused the V2R to be unable to leave its holding site inside the cell to get to its work site on the cell membrane surface.
Their research did enable them to conclude that the NDI causing gene was the same as the mutated V2R gene. The fact that other researchers have found other types of mutations in the V2R genes of North American NDI patients confirms the status of mutated V2R genes as causative for NDI and rules out the notion that all North American cases of NDI came from the original Ulster Scot family.