Human variants in renal polycystins (PKD1, PKD2) are responsible for most forms of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disorder without curative drug treatment. Renal polycystins form ion channels in primary cilia, but our understanding of their molecular dysregulation caused by disease-associated variants is limited. Using cryo-electron microscopy (cryo-EM), primary cilia electrophysiology and super-resolution analysis, we investigated the mechanistic impact and pathogenic potential of the disease-associated PKD2 missense variant (D511V) located within the channels voltage sensor domain. Our findings define how this mutation neutralizes critical transmembrane charge interactions, which attenuates PKD2 protein stability resulting in abolished ciliary channel trafficking and function in membranes. To assess the pathogenic effect of this variant in vivo, we generated novel mouse strains carrying the analogous PKD2 mutation in combination with a conditional floxed allele that exhibit renal tubule primary cilia degeneration and develop rapid renal cysts. Our results establish a clear direct correlation between the in vitro molecular dysfunction and phenotypic in vivo consequences while providing a valuable tool to evaluate ADPKD therapeutic interventions.
Outeda, P., Wang, Q., Vien, T., Esarte Palomero, O., Kimura, L., Summers, P., Watnick, T., Qian, F., Cao, E., DeCaen, P. G.
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