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A Truncated Polycystin-2 Protein Causes Polycystic Kidney Disease and Retinal Degeneration in Transgenic Rats

Anna Rachel Gallagher^*, Sigrid Hoffmann, Nelson Brown^*, Anna Cedzich^*,, Sujatha Meruvu^*, Dirk Podlich, Yuxi Feng, Vera Könecke^*, Uwe de Vries^*, Hans-Peter Hammes, Norbert Gretz and Ralph Witzgall^*

^* Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, and Medical Research Center and Department of Internal Medicine V, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany

Address correspondence to: Ralph Witzgall, University of Regensburg, Institute for Molecular and Cellular Anatomy, Universitätsstrae 31, 93053 Regensburg, Germany. Phone: +49-0-941-943-2821; Fax: +49-0-941-943-2868; E-mail: ralph.witzgall{at}vkl.uni-regensburg.de

Received for publication September 21, 2005. Accepted for publication July 21, 2006.

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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673