Autosomal Recessive Nephrogenic Diabetes Insipidus Caused by an Aquaporin-2 Mutation
| Title: | Autosomal Recessive Nephrogenic Diabetes Insipidus Caused by an Aquaporin-2 Mutation |
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| Authors: | Hochberg, Ze'ev; van Lieburg, Angenita; Even, Lea; Brenner, Benjamin; Lanir, Naomi; van Oost, Bernard A.; Knoers, Nine |
| Publisher: | Journal of Clinical Endrocrinology and Metabolism |
| Date Published: | February 01, 1997 |
| Reference Number: | 9 |
Vasopressin V2 receptors, expressed from an x-chromosomal gene, are involved in antidiuresis, but also in release of coagulation factor VIII and von Willebrand factor (vWF). The present study describes autosomal recessive nephrogenic diabetes insipidus (NDI) in a large cluster of patients in Israel's Lower-Galilee. Evidence for an intact V2 receptor was concluded by their normal increase in factor VIII and vWF after desmopressin infusion. Thus, in these patients a defect in the pathway beyond the V2 receptor was suspected. The recent cloning of the human Aquaporin-2 gene enabled us to test this gene as a candidate for such a postreceptor defect. Direct sequencing of the Aquaporin-2 gene revealed a G298T substitution causing a Gly100Stop nonsense mutation in the third transmembrane region. Because this putative disease-causing mutation was identified in index patients of different families, we suggest that all patients are descendants of a common ancestor. Thus, this new entity is characterized by an autosomal recessive NDI. The differential response of clotting factors and urine osmolality to desmopressin may provide a simple tool for clinical diagnosis of a V2-postreceptor defect. The early stop-codon of Aquaporin-2 results in complete resistance to vasopressin antidiuretic effect.
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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)
X-linked NDI is the most frequent inherited form of the disease, but NDI may also be inherited via a mutation of a gene that is located on a non-sex chromosome (i.e., an autosomal chromosome). The aquaporin-2 (AQP2) gene is located in autosomal chromosome 12. AQP2 is a water transporter in the kidney, that is activated by VP to reabsorb water from the kidney tubule volume to the tubules cell. Researchers have found that mutations in AQP2 can result in NDI. So now researchers know that if a patient shows symptoms of inherited NDI, they must consider that the mutation may be in one of two genes: V2 or AQP2.
Hochberg, et al., report on a total of 11 patients from three closely related families of Bedouin-Arab origin with the autosomal recessive form of NDI. They had first tested for mutated V2R genes, but since the patients showed a normal increase in their blood clotting factors after being infused with a synthetic analog of AVP called DDAVP, Hochberg, et al., concluded the V2R gene was functional. They then analyzed the AQP2 gene and discovered it had a nonsense mutation: a type of mutation that causes a premature termination of the gene's genetic sequence and results in a truncated gene that releases nonfunctional polypeptides. It is difficult to imagine how such a truncated protein could perform its function of making cell membranes more water permeable. This mutation has never been described before.
In closing, the authors point out how the kidneys of patients with an AQP2 defect will not respond to vasopressin, but their blood clotting factors will. In short, people with the AQP2 defect will continue to produce dilute urine while producing a normal quantity of blood clotting factors after receiving an infusion of DDAVP. This is in contrast to people with V2R mutations: neither their kidneys nor blood clotting factors respond to DDAVP. This response could serve as a simple diagnostic method used on people presenting NDI symptoms if there is not a molecular geneticist available.