1999 European Regional Conference Proceeding
May 12 - 16, 1999
| Conference: | 1999 European Regional Conference |
|---|---|
| Title: | A mouse model for X-linked nephrogenic diabetes insipidus |
| Authors: | Yun, June; Schoneberg, Torsten; Liu, Jie; Sheng, Hui; Grinberg, Alexander; Deng, Chu-xia; Wess, Jurgen |
| Institutions: | NIH, National Institute of Diabetes and Digestive and Kidney Diseases, University of Leipzig, University of Maryland School of Medicine, National Institute of Child Health and Human Development, National Institutes of Health, National Institutes of Health, NIDDK |
X-linked nephrogenic diabetes insipidus (XNDI) is a rare genetic disorder characterized by the failure of the kidney to concentrate urine. It has been demonstrated that XNDI is caused by inactivating mutations within the V2 vasopressin receptor (V2R) gene. At present, no animal model exists that mimics the genetic defect present in XNDI patients. However, the availability of such a model would greatly facilitate the testing of new strategies in the treatment of XNDI. Taking advantage of recent advances in gene targeting technology, we, therefore, decided to introduce a V2R mutation (Glu242->Stop) into the mouse genome that is known to cause XNDI in humans (Wildin et al., Am. J. Hum. Genet., 55, 266-277, 1994). This mutation is predicted to lead to the synthesis of a mutant version of the V2R that is truncated within the third intracellular loop. A targeting construct harboring the Glu242->Stop nonsense mutation was electroporated into male mouse embryonic stem cells to replace the wild-type V2R gene with the mutant version via homologous recombination. Using standard transgenic techniques, six highly chimeric male mice were generated, four of which were able to transmit the mutant V2R gene through the germline. F1 generation females heterozygous for the V2R mutation were then mated to wild-type male littermates to generate F2 offspring.
Male F2 mice hemizygous for the V2R mutation were obtained at the expected Mendelian ratio (about 25%). Wild-type and V2R mutant pups showed no obvious differences in morphology and weight at the time of birth. However, by the third day after birth, a clear growth retardation became visible in male mice hemizygous for the V2R mutation. These animals failed to thrive and usually died between four and six days after birth, probably due to dehydration. Consistent with this notion, hematocrit values and sodium plasma levels were significantly increased in these pups. Various different strategies are currently being explored in an attempt to increase the survival rate of the V2R-deficient male pups. Interestingly, most adult females heterozygous for the V2R mutation also showed a clear XNDI phenotype, characterized by reduced urine osmolality, polyuria, and polydipisa. The V2R mutant mice described here will serve as a useful model to study the role of the V2R in kidney physiology and to test novel strategies for the treatment of XNDI.