Cardiac defects and renal failure in mice with targeted mutations in Pkd2

PKD2, mutations in which cause autosomal dominant polycystic kidney disease (1) (ADPKD), encodes an integral membrane glycoprotein(2) with similarity t o calcium channel subunits(1,3). We induced two mutations in the mouse homo logue Pkd2 (ref. 4): an unstable allele (WS25; hereafter denoted pkd2(WS25) ) that can undergo homologous-recombination-based somatic rearrangement to form a null allele; and a true null mutation (WS183; hereafter denoted Pkd2 (-)). We examined these mutations to understand the function of polycystin- 2, the protein product of Pkd2, and to provide evidence that kidney and liv er cyst formation associated with Pkd2 deficiency occurs by a two-hit mecha nism(4-9). Pkd2(-/-) mice die in utero between embryonic day (E) 13.5 and p arturition. They have structural defects in cardiac septation and cyst form ation in maturing nephrons and pancreatic ducts. Pancreatic ductal cysts al so occur in adult pkd2(WS25/-) mice, suggesting that this clinical manifest ation of ADPKD also occurs by a two-hit mechanism. As in human ADPKD, forma tion of kidney cysts in adult pkd2(WS25/-) mice is associated with renal fa ilure and early death (median survival, 65 weeks versus 94 weeks for contro ls). Adult Pkd2(+/-) mice have intermediate survival in the absence of cyst ic disease or renal failure, providing the first indication of a deleteriou s effect of haploinsufficiency at Pkd2 on long-term survival. Our studies a dvance our understanding of the function of polycystin-2 in development and our mouse models recapitulate the complex human ADPKD phenotype.