Normal Fibrinolytic Responses to 1-Desamino-8-D-Arginine Vasopressin in Patients with Nephrogenic Diabetes Insipidus Caused by Mutations in the Aquaporin 2 Gene
| Title: | Normal Fibrinolytic Responses to 1-Desamino-8-D-Arginine Vasopressin in Patients with Nephrogenic Diabetes Insipidus Caused by Mutations in the Aquaporin 2 Gene |
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| Authors: | van Lieburg, Angenita; Knoers, Nine; Mallmann, Rudolf; Proesmans, W.; van den Heuvel, L.P.W.J.; Monnens, Leo A.H. |
| Publisher: | Nephron |
| Date Published: | 1996 |
| Reference Number: | 45 |
Three patients with autosomal-recessive nephrogenic diabetes insipidus (NDI), homozygous for mutations in the aquaporin 2 gene (AQP2), were tested for their fibrinolytic and hemodynamic responses to intravenous administration of 1-desamino-8-D-arginine vasopressin (DDAVP). They all showed an increase of tissue-type plasminogen activator antigen, facial flushing, an increase of heart rate and a decrease of diastolic blood pressure. These results confirm the hypothesis that NDI patients with an AQP2 defect can be discriminated from NDI patients with a vasopressin type 2 receptor defect by their normal extrarenal responses to DDAVP.
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)
When a synthetic analog of AVP called dDAVP is administered, it activates the V2Rs both inside and outside the kidney. The V2Rs inside the kidney are called intrarenal V2Rs and those outside the kidney are called extrarenal V2Rs. dDAVP affects the intrarenal V2Rs by helping them begin the urine concentration process. It effects the extrarenal V2Rs by causing the blood vessels to dilate and increase blood factors essential to the formation and dissolution of blood clots.
Nephrogenic diabetes insipidus (NDI) is a kidney disorder characterized by the kidney's inability to respond to AVP. Since the kidney cannot respond to AVP, the molecular sequence that AVP initiates does not happen, so the cells in the kidney collecting duct are not able to reabsorb water and thus concentrate urine.
The molecular basis for the most common form of inherited NDI, X-linked NDI, are mutations of the V2R gene which result in defective V2Rs unable to bind with AVP. Since the patients' V2Rs cannot bind with AVP, administering an extra, synthetic AVP -- dDAVP -- has no therapeutic effect. And since the genetic defect is general (i.e. it affects the V2Rs both inside and outside the kidney), the V2Rs outside the kidney do not respond to dDAVP either.
However, there are some patients with NDI whose extrarenal V2Rs function normally, as indicated by their response to DDAVP. These patients' blood vessels dilate and there is an increase in the blood factors involved in the formation and dissolution of blood clots. The genetic basis for this form of NDI was discovered when researchers found that their patients had faulty AQP2s due to mutations of the AQP2 gene. These defective AQP2s could not insert themselves in cell membranes and this prevented the kidneys from being able to reabsorb water and concentrate urine.
VanLieburg, et al., had observed an NDI patient with a normal extrarenal response to DDAVP and then discovered he had mutated AQP2 genes. Since this was the only NDI patient with a proven AQP2 defect whose extrarenal responses were studied, the authors gave dDAVP tests to three other NDI patients with distinct AQP2 mutations to see if they too had normal extrarenal responses to dDAVP.
These patients did exhibit normal responses. They showed increased heart rates, facial flushing, decreased diastolic blood pressure, and a significant rise in specific blood factors. A control group of six NDI patients with distinct V2R gene mutations showed no such response. Since the symptoms of NDI are the same no matter if the NDI is caused by mutations in the V2R or AQP2, the authors suggest that administering DDAVP and then noting the patient's extrarenal response to it would be one way of distinguishing the molecular cause of each patient's NDI.
However, the authors note that using this test to distinguish the molecular basis of NDI in females is more complicated. Females are much less likely to express NDI as a result of a V2R gene mutation because the mutated V2R is recessive and is carried on the X chromosome.
Most genes come in pairs. One of the gene pairs (for example the gene responsible for eye color) comes from the father, and the other gene (responsible for eye color) comes from the mother. If a gene is recessive, both of the pairs of the genes must be the same for the trait the gene carries to express itself. For example, the gene for blue eyes is recessive, so if one of the genes for eye color inherited from the mother is for brown eyes and the one from the father is for blue eyes, then the child will have brown eyes because the brown eye gene is dominant. The child would need to inherit a blue eye gene from both parents in order to have blue eyes because the blue eye gene is recessive.
Females have two X chromosomes, which means they have two V2R genes. If one of their V2R genes is normal and the other is mutated, then the normal V2R gene will express itself and the mutated one will not. This is because the mutated V2R gene is recessive and it normally would take two mutated V2R genes for the women to express V2R-related NDI. Men only have one X chromosome, so if they inherit a mutated V2R gene from their mother, they have no other V2R gene to dominate it and they will express the symptoms of NDI.
The AQP2 gene is on a non-sex gene, which means both males and females have a pair of AQP2 genes. Thus, females are as likely to get and express mutated AQP2 genes as males. But researchers cannot automatically assume that the genetic basis of all NDI female patients must be a mutated AQP2 gene because sometimes the healthy V2R genes are inactivated and the mutant V2R gene (should they have one) takes over.
This inactivation of genes on the X-chromosome is called X-inactivation and can vary between different tissues. In this case it is possible that inactivation of the normal V2R gene occurs in the kidney tissues, whereas in other tissues the mutated V2R-gene is inactivated. Thus, outside the kidney the normal V2R gene could be active and the V2Rs there could respond to dDAVP even though the V2Rs in the kidney could not. So it would seem hazardous to rely solely on the females extrarenal response when trying to diagnose the genetic base of NDI in females.