The PKD/Mhm(cy/؉) rat is a widely used animal model for the study of human autosomal dominant polycystic kidney disease, one of the most common genetic disorders, affecting one in 1000 individuals. We identified a new gene, Anks6, which is mutated (Anks6 (p.R823W) ) in PKD/Mhm(cy/؉) rats. The evidence for a causal link between Anks6 (p.R823W) and cystogenesis is still lacking, and the function of Anks6 is presently unknown. This study presents a novel transgenic rat model that overexpresses the mutated 2.8-kb Anks6 (p.R823W) cDNA in the renal tubular epithelium. The transgenic Anks6 (p.R823W) acts in a dominant-negative fashion and causes a predictable polycystic phenotype that largely mimics the general characteristics of the PKD/Mhm(cy/؉) rats. Cyst development is accompanied by enhanced c-myc expression and continuous proliferation, apoptosis, and de-differentiation of the renal tubular epithelium as well as by a lack of translational up-regulation of p21 during aging. Using Northern blot analysis and in situ hybridization studies , we identified the first 10 days of age as the period during which transgene expression precedes and initiates cystic growth. Thus , we not only provide the first in vivo evidence for a causal link between the novel Anks6 (p.R823W) gene mutation and polycystic kidney disease , but we also developed a new transgenic rat model that will serve as an important resource for further exploration of the still unknown function

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