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

Three founder transgenic mice were generated with a 108 kb human genomic fr agment containing the entire autosomal dominant polycystic kidney disease ( ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2, Two lines were e stablished (TPK1 and TPK3) each with similar to 30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that wa s developmentally regulated, similar to the endogenous pattern, with expres sion during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brai n. Transgenic animals from both lines land the TPK2 founder animal) often d isplayed a renal cystic phenotype, typically consisting of multiple microcy sts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation , characteristic of ADPKD, were also seen. All animals with two copies of t he transgenic chromosome developed cysts and, in total, 48 of the 100 trans genic animals displayed a cystic phenotype, To test the functionality of th e transgene, animals were bred with the Pkd(del34) knockout mouse. Both tra nsgenic lines rescued the embryonically lethal Pkd1(del34/del34) phenotype, demonstrating that human polycystin-1 can complement for loss of the endog enous protein. The rescued animals were viable into adulthood, although mor e than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd(del34/+) animals. The TPK mice have defined a minima l area that appropriately expresses human PKDI, Furthermore, this model ind icates 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.