Human Molecular Genetics Advance Access originally published online on June 16, 2007
Human Molecular Genetics 2007 16(16):1940-1950; doi:10.1093/hmg/ddm141
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Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway
1 Department of Medicine, Division of Nephrology, 2 Department of Molecular Comparative Pathobiology, Johns Hopkins University School of Medicine, Ross 958, 720 Rutland Avenue, Baltimore, MD 21205, USA, 3 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA and 4 Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
* To whom correspondence should be addressed. Tel: +1 4106141650; Fax: +1 4106145129; Email: ggermino{at}jhmi.edu
Received March 9, 2007; Revised May 23, 2007; Accepted May 30, 2007
Polycystic kidney disease (PKD) 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 PKD, we generated a mouse line with a floxed allele of Pkhd1, the orthologue of the gene mutated in human autosomal recessive PKD. 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 PKD. Pkd1+/–; Pkhd1del3-4/del3-4 mice had markedly more severe disease than Pkd1+/+; Pkhd1del3-4/del3-4 littermates. These studies are the first to show genetic interaction between the major loci responsible for human renal cystic disease in a common PKD pathway.
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