Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway

Miguel A. Garcia-Gonzalez, Luis F. Menezes, Klaus B. Piontek, Junya Kaimori, David L. Huso, Terry Watnick, Luiz F. Onuchic, Lisa M. Guay-Woodford, Gregory G. Germino

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79 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1940-1950
Number of pages11
JournalHuman molecular genetics
Issue number16
StatePublished - Aug 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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