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

Guanqing Wu, Glen S. Markowitz, Li Li, Vivette D. D'Agati, Stephen M. Factor, Lin Geng, Sonia Tibara, Jay Tuchman, Yiqiang Cai, Jong Hoon Park, Janet Van Adelsberg, Harry Hou, Raju Kucherlapati, Winfried Edelmann, Stefan Somlo

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Abstract

PKD2, mutations in which cause autosomal dominant polycystic kidney disease (ADPKD), encodes an integral membrane glycoprotein with similarity to calcium channel subunits. We induced two mutations in the mouse homologue 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 liver cyst formation associated with Pkd2 deficiency occurs by a two-hit mechanism. Pkd2(-/-) mice die in utero between embryonic day (E) 13.5 and parturition. they have structural defects in cardiac septation and cyst formation in maturing nephrons and pancreatic ducts. Pancreatic ductal cysts also occur in adult Pkd2(WS25/-) mice, suggesting that this clinical manifestation of ADPKD also occurs by a two-hit mechanism. As in human ADPKD, formation of kidney cysts in adult Pkd2(WS25/-) mice is associated with renal failure and early death (median survival, 65 weeks versus 94 weeks for controls). Adult Pkd2(+/-) mice have intermediate survival in the absence of cystic disease or renal failure, providing the first indication of a deleterious effect of haploinsufficiency at Pkd2 on long-term survival. Our studies advance our understanding of the function of polycystin-2 in development and our mouse models recapitulate the complex human ADPKD phenotype.

Original languageEnglish (US)
Pages (from-to)75-78
Number of pages4
JournalNature Genetics
Volume24
Issue number1
DOIs
StatePublished - 2000

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Renal Insufficiency
Autosomal Dominant Polycystic Kidney
Heart Failure
Mutation
Cysts
Survival
Alleles
Pancreatic Cyst
Kidney
Haploinsufficiency
Pancreatic Ducts
Homologous Recombination
Nephrons
Membrane Glycoproteins
Calcium Channels
Parturition
Phenotype
Liver
Proteins
polycystic kidney disease 2 protein

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Wu, G., Markowitz, G. S., Li, L., D'Agati, V. D., Factor, S. M., Geng, L., ... Somlo, S. (2000). Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nature Genetics, 24(1), 75-78. https://doi.org/10.1038/71724

Cardiac defects and renal failure in mice with targeted mutations in Pkd2. / Wu, Guanqing; Markowitz, Glen S.; Li, Li; D'Agati, Vivette D.; Factor, Stephen M.; Geng, Lin; Tibara, Sonia; Tuchman, Jay; Cai, Yiqiang; Park, Jong Hoon; Van Adelsberg, Janet; Hou, Harry; Kucherlapati, Raju; Edelmann, Winfried; Somlo, Stefan.

In: Nature Genetics, Vol. 24, No. 1, 2000, p. 75-78.

Research output: Contribution to journalArticle

Wu, G, Markowitz, GS, Li, L, D'Agati, VD, Factor, SM, Geng, L, Tibara, S, Tuchman, J, Cai, Y, Park, JH, Van Adelsberg, J, Hou, H, Kucherlapati, R, Edelmann, W & Somlo, S 2000, 'Cardiac defects and renal failure in mice with targeted mutations in Pkd2', Nature Genetics, vol. 24, no. 1, pp. 75-78. https://doi.org/10.1038/71724
Wu G, Markowitz GS, Li L, D'Agati VD, Factor SM, Geng L et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nature Genetics. 2000;24(1):75-78. https://doi.org/10.1038/71724
Wu, Guanqing ; Markowitz, Glen S. ; Li, Li ; D'Agati, Vivette D. ; Factor, Stephen M. ; Geng, Lin ; Tibara, Sonia ; Tuchman, Jay ; Cai, Yiqiang ; Park, Jong Hoon ; Van Adelsberg, Janet ; Hou, Harry ; Kucherlapati, Raju ; Edelmann, Winfried ; Somlo, Stefan. / Cardiac defects and renal failure in mice with targeted mutations in Pkd2. In: Nature Genetics. 2000 ; Vol. 24, No. 1. pp. 75-78.
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