Mutations in the Vasopressin V2 Receptor and Aquaporin-2 Genes in 12 Families with Congenital Nephrogenic Diabetes Insipidus
| Title: | Mutations in the Vasopressin V2 Receptor and Aquaporin-2 Genes in 12 Families with Congenital Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Vargas-Poussou, Rosa; Forestier, Lionel; Dautzenberg, Marie Dominique; Niaudet, Patrick; Dechaux, Michele; Antignac, Corinne |
| Publisher: | Journal of American Society of Nephrology |
| Date Published: | December 01, 1997 |
| Reference Number: | 157 |
Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by renal tubular insensitivity to the antidiuretic effect of arginine vasopressin (AVP). In a large majority of the cases, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remaining cases, the disease is autosomal recessive or dominant and, for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. Fourteen probands belonging to 12 families were analyzed by single-strand conformational polymorphism and direct sequencing of the AVPR2 and AQP2 genes. Ten mutations of the AVPR2 gene (six previously reported mutations and four novel mutations: G107E, W193X, L43P, and 15delC) were identified. Three mutations of the AQP2 gene were also identified in two patients: the first patient is homozygous for the R85X mutation and the second is a compound heterozygote for V168 M and S216P mutations. Extrarenal responses to infusion of the strong V2 agonist 1-desamino-8-D-arginine vasopressin allowed AVPR2- and AQP2-associated forms of CNDI to be distinguished in three patients. This test also identified an unexpectedly high urinary osmolality (614 mosmol/kg) in a patient with a P322S mutation of AVPR2 gene and a mild form of CNDI.
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)
The arginine vasopressin 2 receptor (AVPR2) plays a very important part in the kidney's urine concentrating process. It is the molecular structure to which AVP binds and gives the message to begin the urine concentrating process. Normally, the V2 receptor binds with AVP and accepts its message. Then it initiates the next step in the process which ultimately signals a water-transporting protein called aquaporin-2 (AQP2) to travel to and insert itself into the membranes of specific kidney cells. This lets a lot more water than usual flow through these kidney cells, an event essential for urine concentration.
Genes synthesize proteins, but when a gene is mutated, it can produce faulty proteins that range from partially to completely non-functional and therefore can produce some functional disorder. The genes that produce AVPR2 and AQP2 are called the AVPR2 gene and the AQP2 gene. Mutations in either of them can result in CNDI. Mutations can occur at different locations on genes. For example, two people can have CNDI caused by mutations of their AVPR2 gene, yet the mutation in one can be located at one end of the gene, whereas the location of the other can be at the other end.
Vargas-Poussou, et al., studied 14 CNDI patients belonging to 12 unrelated families of diverse ethnic origin. They found ten of the patients had mutations in their AVPR2 genes. Six of the mutations had been found in the same locations as in other CNDI patients, but four had not. Two patients had mutations in their AQP2 gene (one of these patients had two mutations in his AQP2 gene).
Though mutations in these two genes can both result in CNDI, and the CNDI in both instances will express the same symptoms, the gene-related breakdown in the urine-concentrating process will occur at different points in the process depending on which gene is mutated. An AVPR2 mutation causes a breakdown at the beginning of the process because the AVPR2 doesn't bind with AVP. In an AQP2 mutation, the AVPR2 binds with AVP and the process begins, but the AQP2s do not travel to the cell membranes to make them more water permeable. Since mutations in the AVPR2 gene do not allow AVP binding to take place, the CNDI patient with this type of mutation will not respond to infusions of synthetic AVP, whereas the patient with an AQP2 gene mutation will. There are additional responses in how the blood moves and coagulates in response to synthetic AVP that allow researchers to distinguish between AQP2 gene and AVPR2 gene-associated CNDI. These responses are normal in patients with AQP2 mutations and abnormal in patients with AVPR2 mutations.
In Vargas-Poussou's, et al., study, this response pattern was maintained. Those with AVPR2 mutations did not respond to synthetic AVP and the two patients with AQP2 mutations did. There was one partial, though intriguing, exception. One CNDI patient with an AVPR2 mutation did respond to synthetic AVP; his urine became more concentrated. This patient had mild symptoms. The patient's AVPR2 gene was mutated at a location called the seventh transmembrane domain (please look at diagram of AVPR2), and the type of mutation was called P322S. Previous research had discovered this mutation in another patient who also had mild symptoms and showed a partial response to synthetic AVP