| Title: | Disruption of Polycystin Ciliary Localization and Channel Function by Autosomal Dominant Polycystic Kidney Disease-Causing Polycystin-1 Variants |
| Journal: | Journal of the American Society of Nephrology |
| Published: | 10 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41665965/ |
| DOI: | https://doi.org/10.1681/asn.0000001008 |
| URL: | https://pubmed.ncbi.nlm.nih.gov/41665965/ |
Publication 21460
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
KEY POINTS: We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease. All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function. Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding.</p>
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).</p>
METHODS: We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function.</p>
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.</p>
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.</p>
7 Keywords
- Animals
- Cilia
- Humans
- Mutation
- Polycystic Kidney, Autosomal Dominant
- Protein Transport
- TRPP Cation Channels
14 Authors
- Kotdaji Ha
- Gabriel B. Loeb
- Meyeon Park
- Mohona Gupta
- Yukako Akiyama
- Jillian Argiris
- Aide Pinedo
- Christine Haewon Park
- Nadav Brandes
- Fnu Ritu
- Chun Jimmie Ye
- Willow Coyote-Maestas
- Jeremy F. Reiter
- Markus Delling
1 Application
| Application ID | Title |
|---|---|
| 78378 | Fine-mapping kidney function variants |
Enabling scientific discoveries that improve human health