{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "Juan Wang"
    },
    {
      "name": "Carlos Nava Cruz"
    },
    {
      "name": "Jonathon D Walsh"
    },
    {
      "name": "Elizabeth desRanleau"
    },
    {
      "name": "Inna A Nikonorova",
      "orcid": "0000-0001-8498-848X"
    },
    {
      "name": "Maureen M Barr",
      "orcid": "0000-0003-4483-2952"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/evyj0qmyc93jz.bib",
  "cited_by": 0,
  "doi": "10.1093/genetics/iyag182",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13732696/",
  "id": "evyj0qmyc93jz",
  "issns": [
    "0016-6731",
    "1943-2631"
  ],
  "landing_url": "https://doi.org/10.1093/genetics/iyag182",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/SCI01140"
    ],
    [
      "heading",
      "AcademicSubjects/SCI01180"
    ],
    [
      "heading",
      "Featured"
    ],
    [
      "heading",
      "Investigation"
    ],
    [
      "openalex",
      "1311|Genetic and Kidney Cyst Diseases"
    ]
  ],
  "openalex": "W7168187566",
  "pdf_url": null,
  "pmcid": "PMC13732696",
  "pmid": "42441958",
  "published": "2026-07-13",
  "publisher": "Oxford University Press",
  "ris": "https://research.draconitic.com/paper/evyj0qmyc93jz.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:22:38Z",
      "native_id": "PMC13732696",
      "source": "pmc",
      "url": "https://doi.org/10.1093/genetics/iyag182"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genetic and Kidney Cyst Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "A C. elegans model for functional analysis of conserved ADPKD variants in cilia, extracellular vesicles, and sensory signaling",
  "title_text": "A C. elegans model for functional analysis of conserved ADPKD variants in cilia, extracellular vesicles, and sensory signaling",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:22:38Z",
  "url": "https://research.draconitic.com/paper/evyj0qmyc93jz",
  "venue": "Genetics",
  "versions": []
}