Molecular and Cellular Defects in Nephrogenic Diabetes Insipidus
| Title: | Molecular and Cellular Defects in Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Knoers, Nine; van Os, Carel |
| Publisher: | Current Opinion in Nephrology and Hypertension |
| Date Published: | July 01, 1996 |
| Reference Number: | 18 |
Nephrogenic diabetes insipidus is a rare genetic disorder characterized by insensitivity of the distal nephron to the antidiuretic effect of arginine vasopressin. Two different molecular defects underlying this disease have so far been identified. Mutations in the gene encoding the vasopressin type-2 receptor cause the X-chromosomal form of the disease, whereas mutations in the gene encoding the vasopressin-dependent water channel aquaporin-2 are responsible for the autosomal recessive, and (in some cases) an autosomal dominant type of the disease. Functional analysis of naturally occurring mutations in the vasopressin type-2 receptor and aquaporin-2 have increased the insight into the structure and function of both proteins and have led to substantial progress in understanding the cellular mechanisms underlying the concentrating ability of the kidney. Some female carriers of vasopressin type-2 receptor mutation may show complete manifestation of nephrogenic diabetes insipidus, probably as a result of skewed X-inactivation. The recent findings in nephrogenic diabetes insipidus research have considerable impact for diagnosis of and genetic counselling for this disease.
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)
To more clearly understand NDI, it is helpful to understand the molecular sequence responsible for urine concentration and water reabsorption. AVP binds with its receptor located in the base of the membranes of the principal cells of the kidney collecting duct and inner medulla. This receptor, the vasopressin-2 receptor (V2R), is linked to a stimulatory G-protein. When AVP binds to V2R, the V2R, via the G-protein, stimulates the activation of adenylate cyclase. This increases the level of an important metabolic regulator, cAMP. cAMP signals the water transporting proteins called aquaporin-2 (AQP2) to insert themselves in the apex of the membranes of the principal cells of the kidney collecting duct. This enables these membranes to allow much more water to flow through them than usual, which is how the kidney can reabsorb water and thus concentrate urine. If anything goes wrong at some point in this molecular sequence, the kidney's ability to reabsorb water, concentrate urine and balance body water is compromised.
NDI can be either acquired or inherited. It is most commonly inherited as an X-linked recessive disorder involving mutations of the V2R gene. This means that mutations of the V2R gene produce defective vasopressin-2 receptors which cannot bind with AVP. Thus the process culminating in water reabsorption and urine concentration cannot be initiated. In X-linked recessive disorders the females carry the defective gene on one of their two X chromosomes and can pass it on to either their sons or daughters. But their sons will be much more likely to express the disorder than their daughters, who will become carriers of the defective gene.
Because it is a recessive disorder, the female carriers are much less likely to express NDI than their sons, should these sons inherit the defective gene, because males only have one X chromosome whereas females have two. Females can have X-linked NDI because sometimes both their V2R genes carry different mutations (genes can be mutated in many different ways) or sometimes they have only one mutated V2R gene, but the healthy one gets inactivated and the mutated one can then express itself.
The other, much rarer, form of inherited NDI involves mutations in the AQP2 gene. If the AQP2 gene is mutated it can produce aquaporin-2s that cannot insert themselves into the apex of the collecting duct cell membrane in order to make them more water permeable. The AQP2 gene is not located on a sex chromosome, but on one of the 22 autosomal (i.e. non-sex) chromosome pairs alike in both males and females. It is inherited most often in an autosomal recessive manner. (Genes come in pairs, e.g. there are two AQP2 genes -- one inherited from the mother and one from the father. If a mutation is recessive, both of the genes the offspring inherits from his parents must be defective in order for the characteristic associated with the gene to express itself. In this case, both the AQP2 genes the child receives from his parents must be defective in order for NDI to occur. Though there have been two cases where only one of the parent's AQP2 gene was defective and the offspring still expressed NDI.)
Patients with NDI, whether it is caused by a defective V2R gene or a defective AQP2 gene, express the same symptoms. One way to differentiate the cause is to administer a synthetic analog of AVP to the patient and then measure certain factors involved in the blood clotting process because they too are dependent on normally functioning V2R. If the patient's blood clotting factors respond normally to the synthetic AVP, then the clinician can assume the patient's NDI is due to defective AQP2 genes. If these factors do not respond, then the cause of NDI is most likely defective V2R.