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A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation

Abstract

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.

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Figure 1: Pkd1 dosage is the main genetic determinant of Prkcsh-dependent cyst formation.
Figure 2: Pkd1 and Pkd2 dosage in Sec63-dependent cyst formation.
Figure 3: Impaired biogenesis and trafficking of PC1 in ADPLD.
Figure 4: Late stage tubule dilation in Prkcsh and Sec63 mutant kidneys overexpressing PC1 (a,b).
Figure 5: Nephron segment-specific sensitivity to Pkd1 dosage-dependent proliferation and cyst growth.
Figure 6: Genetic interaction of Pkhd1, Pkd1 and Sec63.
Figure 7: Proteasome inhibitor therapy ameliorates cyst formation following loss of Prkcsh.

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Acknowledgements

Carfilzomib was a kind gift from Proteolix, Inc. This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)/ US National Institutes of Health (NIH) (R01DK51041 and R01DK54053 to S.S. and F31DK083904 to S.V.F.) and a grant from the Mizutani Foundation for Glycoscience (S.S.). We are grateful for support from the Nephrology Training Grant (T32DK007276) to S.V.F. and the Joseph LeRoy and Ann C. Warner Fund (S.S.). The authors are members of the Yale PKD Center (P50DK57328). We are grateful for Core services from the Yale O'Brien Kidney Center (P30DK079310).

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S.V.F. co-designed the study, performed the experiments and co-wrote the manuscript. X.T. and M.M. generated the mouse models. A.-R.G. performed experiments, participated in the experimental design and assisted in manuscript preparation. S.N., S.H.L., Y.C. and L.G. carried out experiments. C.M.C. participated in the proteasome inhibitor studies. S.S. came up with the study design and co-wrote the manuscript.

Corresponding author

Correspondence to Stefan Somlo.

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Fedeles, S., Tian, X., Gallagher, AR. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet 43, 639–647 (2011). https://doi.org/10.1038/ng.860

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