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Kidney Week

Abstract: PO1224

Mutation Position and Genetic Background Modulate Disease Expression in Pkhd1 Mouse Models

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Odinakachukwu, Maryanne, Children's National Research Institute, Washington, District of Columbia, United States
  • Yang, Chaozhe, Children's National Research Institute, Washington, District of Columbia, United States
  • Bebok, Zsuzsanna M., The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Guay-Woodford, Lisa M., Children's National Research Institute, Washington, District of Columbia, United States

Multiple Pkhd1 mutant mouse models have been generated by gene-targeting methods (del3-4, del67) or resulted from spontaneous mutations (cyli). When these mutations are homozygous on inbred backgrounds (DBA/2J (D2); C57BL/6 (B6)), there is either no renal cystic disease or very mild dilatation of the PCTs rather than CCDs. A recent ARegPKD report showed that the position of human PKHD1 mutations correlates with ARPKD kidney and liver disease severity (Burgmaier, KI 2021). In the current study, we examined the impact of age, mutation position, and mixed genetic background on kidney, liver, and pancreatic disease in Pkhd1 mutants.


D2-Pkhd1cyli/+; B6-Pkhd1del3-4/+ and B6-Pkhd1del67/+ mouse lines. Intercross strategy to generate a suite of F2 mutants on mixed genetic backgrounds (D2.B6). Histopathological analysis of the kidney, liver, and pancreas from 18-month-old, nulliparous mutant females.


D2.B6-Pkhd1cyli/cyli mutants expressed both marked dilatation of the CCDs and liver ductal plate malformation (DPM); no pancreatic cysts were observed. Similarly, D2.B6-Pkhd1del3-4/del3-4 mutants expressed corticomedullary cysts, involving DCTs and CCDs and DPM lesion but no pancreatic cysts. In contrast, D2.B6-Pkhd1cyli/del3-4 compound heterozygotes had occasional dilated DCTs, a marked DPM lesion, and diffuse cyst formation in the pancreatic ducts. The D2.B6-Pkhd1cyli/del67 and D2.B6-Pkhd1del67/del67 mutants had occasional dilated DCTs, no DPM or pancreatic cysts.


Age, genetic background, and mutation position modulate organ-specific disease expression in Pkhd1 mutants. On the mixed D2.B6 background both cyli and del3-4 aged F2 mutants develop CCD cysts, similar to human PKHD1 renal disease. Surprisingly, D2.B6-Pkhd1cyli/del3-4 mice had minimal kidney pathology but marked pancreatic duct cysts, suggesting that genetic background differentially modulates kidney and pancreatic cystic phenotypes. Mice heterozygous or homozygous for the del67 mutation expressed minimal kidney, liver, or pancreatic cystic changes. Thus, defects at the 3’ end of Pkhd1 appear to have minimal pathobiological impact, that is not influenced by age or the mixed D2.B6 genetic background. These findings will inform our experimental strategies to identify organ-specific Pkhd1 genetic modifiers.


  • NIDDK Support