Two Novel Mutations in the Vasopressin V2 Receptor Gene in Patients with Congenital Nephrogenic Diabetes Insipidus
| Title: | Two Novel Mutations in the Vasopressin V2 Receptor Gene in Patients with Congenital Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Oksche, Alexander; Dickson, MD, John; Schulein, Ralf; Seyberth, M.D., Hannsjorg W.; Muller, Michael; Rascher, MD, Wolfgang; Birnbaumer, Mariel; Rosenthal, Walter |
| Publisher: | Biochemical and Biophysical Research Communications |
| Date Published: | November 30, 1994 |
| Reference Number: | 86 |
Families with congenital nephrogenic diabetes insipidus were analyzed with regard to mutations in the vasopressin V2 receptor gene. Family 1 shows an X-chromosomal recessive inheritance of the disease over 4 generations. A patient from this family was found to have a T-->A transversion at nucleotide 1095, predictive for a substitution of serine 167 (which is highly conserved among G-protein-coupled receptors), by threonine. Both the mutant and the normal allele were detected in the maternal genome. The patient's healthy brother was homozygous for the normal allele. The patient from family 2 showed a T-->C transition at nucleotide 727, predictive for a substitution of leucine 44 by proline. Analysis of the maternal genome revealed homozygosity for the normal allele. Thus a de novo mutation seems to have occurred. The nature and site of the mutation in family 2 suggest that it is responsible for the patient's disease.
[Published erratum appears in Biochem Biophy Res Commun 1995 Feb 27; 207(3):1059]
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)
Mutations of the V2R gene are the cause of X-linked nephrogenic diabetes insipidus (NDI). NDI is a disorder characterized by the inability of the kidneys to respond to AVP. As a result, the kidneys are unable to concentrate urine or reabsorb water passing through the kidney collecting ducts. People with NDI are constantly passing large volumes of urine and drinking large amounts of water to compensate for this excessive body water loss.
Many different mutations of the V2R gene have been identified. Each different V2R gene mutation alters the structure of the respective V2R in a different way. And often, the different structural alterations impair the functional abilities of the respective V2Rs in different ways.
If you think of the V2R as a beaded string (the beads are amino acids), a major portion of the string lies within the cell membrane in seven distinct coiled folds called transmembranes 1 - 7. Part of the V2R snakes outside the membrane into the extracellular environment, forming three curves called extracellular loops 1 - 3. Part of it snakes inside the cell to form three curves called intracellular loops 1 - 3. One end of the V2R, called the amino-terminus, lies outside the cell with the extracellular loops. The other end, called the carboxy-terminus, lies inside the cell with the intracellular loops. (You can look at a diagram of a V2R for a clearer understanding.)
Oksche, et al., analyzed the V2R genes of two unrelated families with one or more members who had NDI. Family 1 had NDI in the family for four generations. It was transmitted in an X-linked recessive pattern. In this pattern, the mutated V2R gene is carried on one of the mother's two X chromosomes. Though females carry the disorder, they normally do not express the symptoms of the disorder severely, if at all. This is because they have a healthy V2R gene on their other X chromosome which codes for enough healthy V2Rs to successfully bind with AVP. But if a mother has a mutated V2R gene on one of her X-chromosomes and passes that chromosome on to her son, he will express the full symptoms of NDI. This is because males only have one X-chromosome, which they inherit from their mother.
The V2R gene mutation in family 1 resulted in a substitution of the amino acid, threonine, for the amino acid, serine, in position 167 (i.e. the 167th amino acid of the V2R). This amino acid exchange occurred in transmembrane domain 4. As expected, the mother of the male NDI patient had both the mutated V2R gene and a healthy V2R gene, whereas the patient had the mutated V2R gene only. His healthy brother had inherited the normal V2R gene from his mother.
Family 2 did not have a history of NDI, though the male patient, who had no siblings, had all the symptoms of NDI. The patient's mother had a normal V2R gene on each of her X chromosomes. But the patient's V2R gene was mutated. This mutation resulted in a V2R with the amino acid, proline, where the amino acid, leucine, should have been in the first transmembrane domain. It appears that this new mutation, which occurred in the mother's ovum, is responsible for this patient's NDI.