Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Genetics volume 24, pages 75–78 (2000)Cite this article

Abstract

PKD2, mutations in which cause autosomal dominant polycystic kidney disease1 (ADPKD), encodes an integral membrane glycoprotein2 with similarity to calcium channel subunits1,3. We induced two mutations in the mouse homologue Pkd2 (ref.4): an unstable allele (WS25; hereafter denoted Pkd2WS25) 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 mechanism4,5,6,7,8,9. 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 Pkd2WS25/− 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 Pkd2WS25/− 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 Pkd2on 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Kidney development in Pkd2−/− mice.
Figure 2: Pancreas in Pkd2-mutant mice.
Figure 3: Cardiac development in Pkd2−/− mice.
Figure 4: Renal failure and reduced survival in Pkd2-mutant mice.

Similar content being viewed by others

References

  1. Mochizuki, T. et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272, 1339–1342 (1996).

    Article  CAS  Google Scholar 

  2. Cai, Y. et al. Identification and characterization of polycystin-2, the PKD2 gene product. J. Biol. Chem. 274, 28557–28565 (1999).

    Article  CAS  Google Scholar 

  3. Chen, X.Z. et al. Polycystin-L is a calcium-regulated cation channel permeable to calcium ions. Nature 401, 383–386 (1999).

    CAS  PubMed  Google Scholar 

  4. Wu, G. et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177–188 (1998).

    Article  CAS  Google Scholar 

  5. Qian, F., Watnick, T.J., Onunchic, L.F. & Germino, G.G. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87, 979–987 (1996).

    Article  CAS  Google Scholar 

  6. Brasier, J.L. & Henske, E.P. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J. Clin. Invest. 99, 194–199 (1997).

    Article  CAS  Google Scholar 

  7. Koptides, M., Hadjimichael, C., Koupepidou, P., Pierides, A. & Constantinou, D.C. Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease. Hum. Mol. Genet. 8, 509–513 (1999).

    Article  CAS  Google Scholar 

  8. Pei, Y. et al. Somatic PKD2 mutations in individual kidney and liver cysts support a “two-hit” model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 10, 1524–1529 (1999).

    CAS  PubMed  Google Scholar 

  9. Torra, R. et al. A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2. Am. J. Hum. Genet. 65, 345–352 (1999).

    Article  CAS  Google Scholar 

  10. Emmons, S. & Somlo, S. Mating, channels and kidney cysts. Nature 401, 339–340 (1999).

    Article  CAS  Google Scholar 

  11. The International Polycystic Kidney Disease Consortium. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81, 289–298 (1995).

  12. Hughes, J. et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genet. 10, 151–160 (1995).

    Article  CAS  Google Scholar 

  13. Qian, F. et al. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genet. 16, 179–183 (1997).

    Article  CAS  Google Scholar 

  14. Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V.P. & Walz, G. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc. Natl Acad. Sci USA 94, 6965–6970 (1997).

    Article  CAS  Google Scholar 

  15. Markowitz, G.S. et al. Polycystin-2 expression is developmentally regulated. Am. J. Physiol. 277, F17–F25 (1999).

    CAS  PubMed  Google Scholar 

  16. Gittes, G.K., Galante, P.E., Hanahan, D., Rutter, W.J. & Debase, H.T. Lineage-specific morphogenesis in the developing pancreas: role of mesenchymal factors. Development 122, 439–447 (1996).

    CAS  PubMed  Google Scholar 

  17. Lu, W. et al. Perinatal lethality with kidney and pancreas defects in mice with a targeted Pkd1 mutation. Nature Genet. 17, 179–181 (1997).

    Article  CAS  Google Scholar 

  18. Rossant, J. Mouse mutants and cardiac development: new molecular insights into cardiogenesis. Circ. Res. 78, 349–353 (1996).

    Article  CAS  Google Scholar 

  19. Ranger, A.M. et al. The transcription factor NF-ATc is essential for cardiac valve formation. Nature 392, 186–190 (1998).

    Article  CAS  Google Scholar 

  20. Clark, T.G. et al. The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development 126, 2631–2642 (1999).

    CAS  PubMed  Google Scholar 

  21. Conway, S.J., Henderson, D.J., Kirby, M.L., Anderson, R.H. & Copp, A.J. Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. Cardiovasc. Res. 36, 163–173 (1997).

    Article  CAS  Google Scholar 

  22. Fishman, M.C. & Chien, K.R. Fashioning the vertebrate heart: earliest embryonic decisions. Development 124, 2099–2117 (1997).

    CAS  PubMed  Google Scholar 

  23. Olson, E.N. & Srivastava, D. Molecular pathways controlling heart development. Science 272, 671–676 (1996).

    Article  CAS  Google Scholar 

  24. Torra, R. et al. Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease. Clin. Nephrol. 47, 19–22 (1997).

    CAS  PubMed  Google Scholar 

  25. Hateboer, N. et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 353, 103–107 (1999).

    Article  CAS  Google Scholar 

  26. Huston, J., Torres, V.E., Sulivan, P.P., Offord, K.P. & Wiebers, D.O. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. J. Amer. Soc. Nephrol. 3, 1871–1877 (1993).

    Google Scholar 

  27. Bardaji, A. et al. Left ventricular mass and diastolic function in normotensive young adults with autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 32, 970–975 (1998).

    Article  CAS  Google Scholar 

  28. Stockelman, M.G. et al. Chronic renal failure in a mouse model of human adenine phosphoribosyltransferase deficiency. Am. J. Physiol. 275, F154–F163 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Ward for expert technical assistance; E. Burns and the Jacobi Medical Center Clinical Chemistry Labs for serum chemistry determinations; and M. Brueckner for helpful discussions. This work was supported by grants from the NIH (1R01 DK54053) and Albert Einstein Human Genome Program to S.S. and from the New York/New Jersey Affiliate of the National Kidney Foundation to G.S.M.

Author information

Author notes

  1. Guanqing Wu, Yiqiang Cai & Stefan Somlo

    Present address: Section of Nephrology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

Authors and Affiliations

  1. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

    Guanqing Wu, Li Li, Sonia Tibara, Jay Tuchman, Yiqiang Cai, Jong Hoon Park & Stefan Somlo

  2. Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA

    Stephen M. Factor

  3. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA

    Harry Hou Jr

  4. Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, USA

    Raju Kucherlapati & Stefan Somlo

  5. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA

    Winfried Edelmann

  6. Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, New York, USA

    Glen S. Markowitz & Vivette D. D'Agati

  7. Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, New York, USA

    Janet van Adelsberg

  8. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Lin Geng

Authors
  1. Guanqing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glen S. Markowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vivette D. D'Agati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen M. Factor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lin Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sonia Tibara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jay Tuchman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yiqiang Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jong Hoon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Janet van Adelsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Harry Hou Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Raju Kucherlapati
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Winfried Edelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Stefan Somlo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Somlo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, G., Markowitz, G., Li, L. et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat Genet 24, 75–78 (2000). https://doi.org/10.1038/71724

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/71724

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing