Nephrogenic Diabetes Insipidus: Identification of the Genetic Defect
| Title: | Nephrogenic Diabetes Insipidus: Identification of the Genetic Defect |
|---|---|
| Authors: | Knoers, Nine; Ouweland, Ans M.W. van den; Dreesen, Jos C.F.M.; Verdijk, Marian A.J.; Monnens, Leo A.H.; van Oost, Bernard A. |
| Publisher: | Pediatric Nephrology |
| Date Published: | October 01, 1993 |
| Reference Number: | 122 |
Congenital nephrogenic diabetes insipidus (NDI) is an X-linked inherited disorder characterized by renal resistance to the antidiuretic hormonal action of arginine vasopressin. The disease gene has been assigned to the subtelomeric region of the X chromosome long arm by demonstrating close linkage between NDI and several X-chromosomal DNA markers. The finding of closely linked genetic markers is useful in the diagnosis of NDI. Receptor studies in patients have indicated that NDI might be due to the absence or an abnormality of the adenylate cyclase-bound vasopressin type 2 receptor. This assumption was supported by the discovery of functional vasopressin V2 receptor activity in somatic cell hybrid cell lines that carried at least the distal part of the human X chromosome long arm. Definite evidence for a V2 receptor defect being the cause of NDI was found in a recent study demonstrating point mutations in the V2 receptor gene from affected individuals. Direct mutation analysis is now applicable for accurate carrier detection and early (prenatal) diagnosis.
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)
In most cases, NDI is inherited in an X-linked fashion. This means females carry, but do not fully express, the disorder. Males who inherit the gene responsible for NDI from their mother express the disorder.
Researchers were able to discover the gene responsible for NDI in several stages. They knew the molecular sequence responsible for water reabsorption and urine concentration:
- AVP binds with the vasopressin-2 receptor (V2R), which is coupled to a stimulatory G-protein.
- When this occurs, the enzyme adenylyl cyclase is stimulated and this increases the metabolic regulator, cAMP.
- cAMP, through a process not completely understood, but probably involving protein kinase A, stimulates specific water-transporting proteins to insert themselves in the membranes of the principal cells of the kidney collecting duct. This makes the cells much more water permeable than usual and is what allows the kidney duct to reabsorb water and concentrate urine.
When the effects of a synthetic analogue of AVP called dDAVP on NDI patients were evaluated, researchers had more evidence that NDI might be due to a V2R defect. Normally, DDAVP induces a number of effects in the blood, none of which occurred in the NDI patients. These effects were assumed to be dependent on V2R activation (as is urine concentration), indicating that the NDI patients' V2Rs were defective both inside and outside the kidney.
Additionally, Knoers, et al., measured V2R activity in laboratory cell cultures containing different parts of the human X-chromosome. These cell cultures responded to AVP by showing V2R binding activity and elevated cAMP production, where the control cell cultures did not. These findings supported the view that the NDI location on the X-chromosome is the V2R gene location.
Finally, the V2R gene has been cloned. This enables the V2R genes of NDI patients to be analyzed and compared to the V2R genes of people without NDI. Researchers found mutations in NDI patients' V2R genes, and this provided the definite evidence that the V2R receptor gene is the NDI gene. It is the molecular basis for X-linked NDI. A 100% accurate diagnosis of NDI patients and carriers is now possible by direct mutational analysis of the V2R gene.