Gallagher, Anna Rachel and Hoffmann, Sigrid and Brown, Nelson and Cedzich, Anna and Meruvu, Sujatha and Podlich, Dirk and Feng, Yuxi and Koenecke, Vera and de Vries, Uwe and Hammes, Hans-Peter and Gretz, Norbert and Witzgall, Ralph (2006) A truncated polycystin-2 protein causes polycystic kidney disease and retinal degeneration in transgenic rats. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 17 (10). pp. 2719-2730. ISSN 1046-6673, 1533-3450
Full text not available from this repository. (Request a copy)Abstract
The cloning of the PKD1 and PKD2 genes has led to promising new insight into the mechanisms that are responsible for cyst development in patients with autosomal dominant polycystic kidney disease. Although the dominant pattern of inheritance would argue for haploinsufficiency, a gain of function, or a dominant negative mechanism, there is good evidence that autosomal dominant polycystic kidney disease behaves like a recessive disease on a cellular level (two-hit mechanism of cystogenesis). For testing of whether other pathomechanisms in addition to the two-hit hypothesis can explain cyst formation, two transgenic rat lines that contain a truncated human polycystin-2 cDNA were generated. The protein product lacks almost the entire COOH-terminus and mimics mutations that frequently are found in patients. The transgene-encoded mRNA could be detected in multiple tissues of both transgenic lines, with the highest expression in the kidney. Both lines present with renal cysts that originate predominantly from the proximal tubule; in the tubular epithelial cells, the epitope-tagged mutant protein was detected in the brush border and in primary cilia. Further evidence of the involvement of primary cilia stems from the finding of retinal degeneration in the transgenic rats and from the fact that stably transfected LLC-PK1 cells that inducibly produced the truncated polycystin-2 protein elaborated shorter cilia. Other experimental approaches, such as a knock-in strategy, will be necessary to validate these results, but this is the first preliminary evidence that cyst formation is due not only to somatic mutations.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MAMMALIAN-CELLS; CYST FORMATION; RENAL-DISEASE; PKD2; GENE; INTERACTS; CHANNEL; EXPRESSION; MUTATIONS; MODEL; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Jan 2021 10:06 |
| Last Modified: | 25 Jan 2021 10:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/33961 |
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