Two Novel Mutations in the Aquaporin-2 and the Vasopressin V2 Receptor Genes in Patients with Congenital Nephrogenic Diabetes Insipidus
| Title: | Two Novel Mutations in the Aquaporin-2 and the Vasopressin V2 Receptor Genes in Patients with Congenital Nephrogenic Diabetes Insipidus |
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| Authors: | Oksche, Alexander; Moller, Andreas; Dickson, MD, John; Rosendahl, Prof. Dr. Werner; Rascher, MD, Wolfgang; Bichet, Daniel G.; Rosenthal, Walter |
| Publisher: | Human Genetics |
| Date Published: | November 01, 1996 |
| Reference Number: | 14 |
The vasopressin V2 receptor (V2R) and the aquaporin-2 genes of two unrelated male patients with congenital nephrogenic diabetes insipidus were analyzed. The V2R gene of the patient of family 1 had the wild-type sequence. Consequently, the coding region of the aquaporin-2 gene including the exon-intron junctions was sequenced. A novel G to T transversion at codon 202, predictive of an exchange of tryptophan 202 by cysteine, was identified. As the mutation occurs at G-1 of the 5' splice donor site of intron 3, aberrant splicing is also likely. The mutation involves one of the supposed water pore-forming loops. Therefore, both aberrant splicing and amino acid substitution are likely to result in a functionally defective protein. Sequencing of the complete V2R gene of the male patient of family 2 revealed a novel single-base deletion at codon 310 (delta C1001), shifting the reading frame to give an altered amino acid sequence beginning at codon 311. The mutation is unique in predicting a C-terminally extended protein (termination after codon 434 in the mutant receptor instead of codon 371 in the wild-type). The deduced mutant protein is likely to be nonfunctional since the amino acid sequence of the seventh transmembrane domain and the C-terminus is altered.
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)
Oksche, et al., report finding two new mutations in NDI patients. One was in the AQP2 gene of a Turkish male. This mutation involved a switch in position of two of the bases that make up the DNA within the gene: guanine (G) and thymine (T). This sort of switch is predicted to result in a substitution of the amino acid cysteine for tryptophan, which in turn will produce a different protein structure than is needed. It is likely that this G to T transversion prevents the gene from attaching correctly to other DNA molecules, though this is difficult to prove. Even if the gene's ability to attach itself is not affected by this mutation, the predicted exchange of tryptophan for cysteine is likely to cause a defective AQP2. The shape of the AQP2 genes includes five loops, two which occur at the bottom and are called intracellular loops, and three which occur at the top and are called extracellular loops. The Turkish male's mutation occurred within the third extracellular loop, which together with the first intracellular loop, helps the AQP2 make the cell membranes water permeable. (Please see diagram of AQP2.)
The second patient, a male of German descent, had a mutation of the V2R gene which involved a deletion of a portion of the gene's genetic sequence, specifically a deletion of
C1001. This mutation, a frameshift mutation, results in the gene making a completely different set of amino acids than expected into a protein. Normally, such a frameshift mutation results in premature termination of the gene's coding sequence. This frameshift mutation resulted in an extension of the coding region. The result of both is the same: a nonfunctional gene.