Three Novel AVPR2 Mutations in Three Japanese Families with X-Linked Nephrogenic Diabetes Insipidus
| Title: | Three Novel AVPR2 Mutations in Three Japanese Families with X-Linked Nephrogenic Diabetes Insipidus |
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| Authors: | Tajima, Toshihiro; Nakae, Jun; Takekoshi, Yasuo; Takahashi, Yutaka; Yuri, Kenji; Nagashima, Teturo; Fujieda, MD, PhD, Kenji |
| Publisher: | Pediatric Research |
| Date Published: | March 01, 1996 |
| Reference Number: | 32 |
We identified three novel mutations of the arginine vasopressin (AVP) V2 receptor (AVPR2) gene in Japanese families with X-linked congenital nephrogenic diabetes insipidus (NDI). In kindred #1 of siblings, a single base deletion of one out of three guanosines (nucleotides 786-788, 786delG) was detected. This deletion shifts the reading frame with an altered amino acid sequence and introduces a premature stop codon (TGA) at position 270. In kindred #2 of siblings and one unrelated additional patient (patient #3), point mutations that change the same Pro residue at codon 322 in the seventh transmembrane domain to either a Ser or His (P322S or P322H) were detected. This P322 residue is well conserved among rat V1 and V2 receptors, the human oxytocin receptor, and other G protein-coupled receptors, and is thought to be important for proper insertion of the receptor into the membrane. The AVPR2 mutations are heterogeneous both in Japanese and Caucasians populations.
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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)
The V2 receptor is the molecular structure that binds with and receives the message of the antidiuretic hormone, arginine vasopressin (AVP). Mutations in this receptor render it unable to bind with AVP, so the kidney cannot concentrate urine properly. This is a hallmark of NDI. More than 63 disease-causing mutations in the V2 receptor gene have been identified in 90 ethnically diverse families with X-linked NDI. Study of several mutant receptors showed these receptors were inactive. That is, they did not pick up the signals from AVP that they were supposed to.
The authors worked with a total of five boy patients with X-linked NDI, two siblings each from two unrelated families and one patient from yet another family. The authors extracted DNA from the patients in order to study their V2 receptor genes. The V2 receptor lives within the membranes of specific cells. The membrane is that thin, permeable band that separates the inside of the cell from the outside. If you think of the V2 receptor as a string, most of it lies inside the membrane in seven distinct folded clumps called transmembrane helices. Part of the string snakes outside the membrane forming three curves called extracellular loops 1, 2, and 3. Part of the string snakes inside the cell, forming intracacellular loops 1, 2, and 3. The head of the string is outside the cell; the tail is inside. (You can look at a diagram of a V2R here.) This string is made of many separate molecular structures such as amino acid s , all lined up in a specific order. If any of these parts are not arranged properly, or if one or more parts are missing, the gene is mutated. Mutations can occur at any point along the V2 receptor gene.
The V2 receptor gene from their patients did not have any gross deletions, but there were oddities. A small portion within the V2 receptor of one of the boys from family number one was missing one out of three guanosines (a component of RNA). This ultimately resulted in the V2 receptor stopping its growth prematurely, thus stopping itself before it could grow its tail end. Also, this V2 receptor gene produced a V2 receptor that had an incomplete third intracellular loop. Since the tail end and a complete third intracellular domain are necessary for the V2 receptor to recognize G proteins (which are a necessary part of the urine concentrating and water balancing process), this strongly indicates that these mutations caused X-linked NDI in the patient.
In patient two, the authors discovered a single nucleotide change in the seventh transmembrane region. The change was from nucleotide CCC to TCC and this resulted in an amino acid substitution (Pro for Ser). Patient number three's mutation resulted from a change in a single base pair in the V2 receptor gene. (The sequence of bases in a gene is the code for protein manufacture, so if the sequence is changed, the protein will be affected.) Like patient two, the Pro amino acid was replaced, not with Ser, however, but with His. In both cases these substitutions from Pro may well be the cause of X-linked NDI in these two boys since previous research indicates the importance of the amino acid Pro for proper functioning of the V2 receptor gene.
The authors close by remarking on the number of different mutations in the V2 receptor gene associated with X-linked NDI, even amidst the same race of people. They conclude that direct analysis of mutations in the V2 receptor gene will be required for each individual with X-linked NDI.