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Human Molecular Genetics, 2000, Vol. 9, No. 18 2617-2627
© 2000 Oxford University Press

A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype

Lynn Pritchard, Jackie A. Sloane-Stanley, Jackie A. Sharpe, Richard Aspinwall, Weining Lu1, Veronica Buckle, Lana Strmecki3, Denise Walker3, Christopher J. Ward3, Charles E. Alpers2, Jing Zhou1, William G. Wood and Peter C. Harris3,+

Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK, 1Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA, 2Department of Pathology, University of Washington Medical Center, Seattle, WA 98195, USA and 3Department of Nephrology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Three founder transgenic mice were generated with a 108 kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease (ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2. Two lines were established (TPK1 and TPK3) each with ~30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brain. Transgenic animals from both lines (and the TPK2 founder animal) often displayed a renal cystic phenotype, typically consisting of multiple microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. All animals with two copies of the transgenic chromosome developed cysts and, in total, 48 of the 100 transgenic animals displayed a cystic phenotype. To test the functionality of the transgene, animals were bred with the Pkd1del34 knockout mouse. Both transgenic lines rescued the embryonically lethal Pkd1del34/del34 phenotype, demonstrating that human polycystin-1 can complement for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1del34/+ animals. The TPK mice have defined a minimal area that appropriately expresses human PKD1. Furthermore, this model indicates that over-expression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease.

+ To whom correspondence should be addressed. Tel: +1 507 266 0541; Fax: +1 507 266 4710; Email: harris.peter@mayo.edu


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