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Human Molecular Genetics Advance Access published online on June 16, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm141
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic Interaction Studies Link Autosomal Dominant And Recessive Polycystic Kidney Disease In A Common Pathway

Miguel A. Garcia-Gonzalez1, Luis F. Menezes1, Klaus B. Piontek1, Junya Kaimori1, David L. Huso2, Terry Watnick1, Luiz F. Onuchic4, Lisa M. Guay-Woodford3 and Gregory G. Germino1,*

1 Department of Medicine, Division of Nephrology 2 Department of Molecular Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Johns Hopkins University School of Medicine, MD, USA 3 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 4 Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil

* Corresponding author: Gregory Germino, Johns Hopkins University School of Medicine, Ross 958, 720 Rutland Avenue, Baltimore, MD 21205, Telephone: 410-614-1650, Telefax: 410-614-5129, E-mail: ggermino{at}jhmi.edu

Received March 9, 2007; Revised May 30, 2007; Accepted May 30, 2007

Polycystic kidney disease describes a heterogeneous collection of disorders that differ significantly with respect to their etiology and clinical presentation. They share, however, abnormal tubular morphology as a common feature, leading to the hypothesis that their respective gene products may function cooperatively in a common pathway to maintain tubular integrity. To study the pathobiology of one major form of human polycystic kidney disease, we generated a mouse line with a floxed allele of Pkhd1, the orthologue of the gene mutated in human autosomal recessive polycystic kidney disease. Cre-mediated excision of exons 3-4 results in a probable hypomorphic allele. Pkhd1del3-4/del3-4 developed a range of phenotypes that recapitulate key features of the human disease. Like in humans, abnormalities of the biliary tract were an invariant finding. Most mice 6 months or older also developed renal cysts. Subsets of animals presented with either perinatal respiratory failure or exhibited growth retardation that was not due to the renal disease. We then tested for genetic interaction between Pkhd1 and Pkd1, the mouse orthologue of the gene most commonly linked to human autosomal dominant polycystic kidney disease. Pkd1+/-;Pkhd1del3-4/del3-4 mice had markedly more severe disease than Pkd1+/+;Pkhd1del3-4/del3-4littermates. These studies are the first to show genetic interaction between the major loci responsible for human renal cystic disease in a common polycystic kidney disease pathway.


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