Background: Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss of function variants in Polycystin-1 (PC1). Methods: We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and Polycystin channel function. Results: We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: 1) localization of PC1 at the primary cilium or 2) Polycystin ion channel activity. Ciliary localization of a subset of Polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels. Conclusions: This study demonstrated that disruptions in Polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for Polycystin-targeted therapies in ADPKD.
Ha et al. (Tue,) studied this question.