ArticleThe Journal of clinical investigation2014
Altered trafficking and stability of polycystins underlie polycystic kidney disease.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed, 158 citations in OpenAlex.
- Review
- Pathophysiological significance of cholesterol in ciliopathies.Fujita medical journal · 2026Article
- A Ciliary Phosphoinositide Pathway Regulates the Dosage of Polycystins in Primary Cilia.Journal of the American Society of Nephrology : JASN · 2026Article
- AbioRxiv : the preprint server for biology · 2026Article
- ADPKD Progression by Variant Type and Molecular Domain Among Participants in the HALT PKD Trial.Clinical journal of the American Society of Nephrology : CJASN · 2025Article
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- Self-cleavage of the GAIN domain of adhesion G protein-coupled receptors requires multiple domain-extrinsic factors.Nature communications · 2025Article
- Genetic and protein structure prediction analyses identify a rare pathogenic PKD1 variant causing autosomal dominant polycystic kidney disease.CEN case reports · 2025Article
- Physiologic mechanisms underlying polycystic kidney disease.Physiological reviews · 2025Review
- Cholesterol ensures ciliary polycystin-2 localization to prevent polycystic kidney disease.Life science alliance · 2025Article
- Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation.American journal of physiology. Cell physiology · 2025Article
- Article
- Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists.bioRxiv : the preprint server for biology · 2024Article
- Emerging mechanistic understanding of cilia function in cellular signalling.Nature reviews. Molecular cell biology · 2024Review
- The ARPKD Protein DZIP1L Regulates Ciliary Protein Entry by Modulating the Architecture and Function of Ciliary Transition Fibers.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Adhesion G Protein-Coupled ReceptorCells · 2024Article
- Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease.Nature communications · 2024Article
- Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.Cell stem cell · 2024Article
- Cilia Provide a Platform for the Generation, Regulated Secretion, and Reception of Peptidergic Signals.Cells · 2024Review
- The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion.Nature communications · 2023Article
40 more citing papers are in PubMed but not listed here.
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16 authors.
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Abstract
The most severe form of autosomal dominant polycystic kidney disease occurs in patients with mutations in the gene (PKD1) encoding polycystin-1 (PC1). PC1 is a complex polytopic membrane protein expressed in cilia that undergoes autoproteolytic cleavage at a G protein-coupled receptor proteolytic site (GPS). A quarter of PKD1 mutations are missense variants, though it is not clear how these mutations promote disease. Here, we established a cell-based system to evaluate these mutations and determined that GPS cleavage is required for PC1 trafficking to cilia. A common feature among a subset of pathogenic missense mutations is a resulting failure of PC1 to traffic to cilia regardless of GPS cleavage. The application of our system also identified a missense mutation in the gene encoding polycystin-2 (PC2) that prevented this protein from properly trafficking to cilia. Using a Pkd1-BAC recombineering approach, we developed murine models to study the effects of these mutations and confirmed that only the cleaved form of PC1 exits the ER and can rescue the embryonically lethal Pkd1-null mutation. Additionally, steady-state expression levels of the intramembranous COOH-terminal fragment of cleaved PC1 required an intact interaction with PC2. The results of this study demonstrate that PC1 trafficking and expression require GPS cleavage and PC2 interaction, respectively, and provide a framework for functional assays to categorize the effects of missense mutations in polycystins.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.