Novel Mutations in the V2 Vasopressin Receptor Gene in Two Pedigrees with Congenital Nephrogenic Diabetes Insipidus
| Title: | Novel Mutations in the V2 Vasopressin Receptor Gene in Two Pedigrees with Congenital Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Yuasa, Hiromitsu; Ito, MD, Masafumi; Oiso, MD, PhD, Yutaka; Kurokawa, Masaei; Watanabe, Tohru; Oda, Yoshihiko; Ishizuka, Toshie; Tani, Nagayuki; Ito, Seiki; Shibata, Akira; Saito, Hidehiko |
| Publisher: | Journal of Clinical Endocrinology and Metabolism |
| Date Published: | August 01, 1994 |
| Reference Number: | 97 |
Novel mutations in the V2 vasopressin receptor gene were identified in two Japanese pedigrees with X-linked congenital nephrogenic diabetes insipidus. The V2 receptor belongs to the family of G-protein-coupled receptors that contain seven distinct transmembrane domains, and the V2 redceptor gene is encoded by three exons. The coding regions amplified by polymerase chain reaction were directly sequenced. In a pedigree, one of four consecutive quanine sequences (nucleotides 528-531) in the second exon was deleted (528delG). This deletion mutation results in a frame shift beginning at codon 154 in the second intracellular domain and a premature termination at codon 161. In another pedigree, a missense mutation (A-->G) was identified at nucleotide position 310 in the second exon. This point mutation, H80R, changes a histidine at codon 80 in the second transmembrane domain to an arginine that is more positively charged than histidine under the neutral environment. Each mutation cosegregated with the phenotype of diabetes insipidus and supposed to be a cause for resistance to arginine vasopressin.
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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)
Each gene is a string of nucleotide bases linked by sugar and phosphate side chains. The four types of bases are adenine (A), cytosine (c), guanine (G), and thymine (T). The sequence of bases in a gene is the code for the protein the gene manufactures. When the sequences of bases in a gene are altered, it is called a mutation, and the mutated gene will produce an altered protein.
Mutations in the V2R gene alter the structure of V2Rs, and this often prevents the altered V2Rs from performing their functions in specific ways, depending on the nature of the mutation.
Imagine the normal V2R as a long, beaded string (the beads are amino acids; there are 371 of them). The majority of the string lies in seven folded clumps, called transmembrane helices, within the cell membrane, the thin strip of tissue separating the inside of the cell from the outside. Part of the V2R snakes outside the cell, forming three curves called extracellular loops 1 - 3. Part of it snakes inside the cell, forming three curves called intracellular loops 1 - 3. One end, called the amino-terminus, lies outside the cell with the extracellular loops. The other end, called the carboxy-terminus, lies inside the cells with the intracellular loops. (You can look at a diagram of a V2R here.)
Yuasa, et al., examined the V2R gene mutations of NDI patients from two unrelated families. In the first mutation, one of four consecutive guanine residues in the V2R gene's second coding region was missing. This deletion causes a premature termination of the V2Rs that are synthesized by this gene.
In the second mutation, a G was where an A should have been at nucleotide position 310 in the V2R gene's second coding region. This resulted in an arginine amino acid being where a histidine amino acid should have been in the second transmembrane region of the V2R.
The researchers did not do expression studies of the defective V2Rs in laboratory cell cultures in order to determine exactly how these alterations in the V2Rs interfered with their ability to carry out their functions. However, the authors could be fairly certain that these mutations were the molecular basis of the patients' NDI.