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Abstract: PO1518

Cystin Deficiency in Cys1cpk/cpk Cells Leads to Marked Reduction in Fibrocystin/Polyductin (FPC)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Zhang, Yiming, University of Alabama at Birmingham, Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Yang, Chaozhe, Children's National Health System, Washington, District of Columbia, United States
  • Bell, Phillip Darwin, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Guay-Woodford, Lisa M., The George Washington University, Washington, District of Columbia, United States
  • Bebok, Zsuzsanna M., University of Alabama at Birmingham, Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States

Human ARPKD (MIM 263200) is caused by mutations in PKHD1 (which encodes FPC), yet mouse Pkhd1 mutations cause minimal renal cystic disease. By contrast, Cys1cpk/cpk (cpk) mice exhibit an ARPKD-like renal phenotype. The function of cystin (encoded by Cys1) is not fully understood, but the protein is found in the cytoplasm, primary cilium, and nucleus. Its N-terminal myristoylation enables membrane-association, and the AxEGG motif is necessary for ciliary targeting, suggesting a function for cystin in vesicular trafficking. To examine whether cystin is a trafficking adaptor for transmembrane ciliary proteins, like FPC, we evaluated FPC expression in wild-type (WT) and cpk mouse kidney cell lines.


Cell lines: Wild-type (WT) and cpk mouse kidney cortical collecting duct cells were developed using mTERT immortalization. We used qRT-PCR, western blotting, morphometry (ImageJ), and protein colocalization with fluorescent confocal microscopy.


While Pkhd1 mRNA levels were similar, FPC protein levels were reduced by 75% in cpk cells relative to WT. In contrast, PC2 protein levels were only reduced by 25% and no differences in acetylated tubulin or other ciliary proteins, e.g. Ift88 or Arl13b, were observed. In cpk cells, both cystin and FPC were absent from primary cilia, but the percentage of cpk cells with primary cilia, ciliary length and thickness were identical to WT cells. These observations suggested that cystin deficiency specifically influenced FPC protein expression and localization. Elevated levels of p62/SQSTM1 expression suggest that enhanced, selective autophagy could explain reduced FPC levels in cpk cells. In support of this proposed mechanism, we observed that proteasome inhibition, which activates autophagy, reduces FPC levels in both WT and cpk cells.


Our studies reveal a patho-mechanistic connection between renal phenotypes in human ARPKD and cpk mice, wherein cystin deficiency is linked to reduction in FPC. Current studies are focused on elucidating mechanisms by which cystin deficiency induces autophagy and loss of FPC. The recent identification of an ARPKD patient with a homozygous CYS1 mutation (bioRxiv 2020 highlights the significance of these studies for human disease.


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