A C. elegans model for functional analysis of conserved ADPKD variants in cilia, extracellular vesicles, and sensory signaling

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ID: 320816
2026
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Abstract
Abstract Interpreting the pathogenic significance of missense variants in human disease gene candidates remains a major challenge in precision medicine. Autosomal dominant polycystic kidney disease (ADPKD), a common cause of kidney failure, results from mutations in PKD1 or PKD2, encoding polycystin-1 and polycystin-2. Here, we establish C. elegans as a platform for the functional classification of PC2 variants by characterizing PKD-2C180S, the C. elegans ortholog of the likely pathogenic human variant PC2C331S. Using CRISPR/Cas9 genome editing with dual-color fluorescent reporters and super-resolution imaging, we show that PKD-2C180S reduces cell-body protein levels, abolishes ciliary and extracellular vesicle (EV) localization, and eliminates sensory function, phenocopying a pkd-2 null allele. In heterozygous animals, PKD-2C180S is recessive and exerts no dominant-negative effect on wild-type PKD-2 trafficking, protein levels, or function, establishing that PKD-2 is haplosufficient in this model. PKD-2C180S also abolishes ciliary and EV localization of the PC1 homolog LOV-1 and reduces LOV-1 cell-body levels, phenocopying pkd-2 null animals, consistent with PC2 acting as a molecular chaperone for PC1 stability and trafficking. Genetic epistasis analysis shows that PKD-2C180S protein levels and ciliary trafficking defects are intrinsic to the mutant protein and independent of lov-1 and the ciliary kinesin-3 klp-6. Quantitative analysis reveals that LOV-1•PKD-2 is more abundant at the ciliary membrane and more efficiently packaged into EVs than PKD-2 alone in lov-1 mutants. We conclude that PC2C331S may perturb protein stability and/or polycystin complex formation prior to ciliary/EV trafficking. This work establishes a C. elegans pipeline for mechanistic classification of conserved ADPKD-associated missense variants.
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Authors Yi-Xiang Wang, Carlos Nava Cruz, Jonathon D. Walsh, Elizabeth desRanleau, Inna A. Nikonorova, Maureen M. Barr
Journal current genetics
Year 2026
DOI
10.1093/genetics/iyag182
URL
https://doi.org/10.1093/genetics/iyag182
Keywords Keywords not found

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