{
  "abstract": "Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulator of low-density lipoprotein (LDL) cholesterol metabolism, yet the functional consequences of many clinically observed PCSK9 variants remain unknown. To establish a rigorous system for quantitative variant assessment, we generated a PCSK9 knockout (KO) HepG2 cell line through CRISPR/Cas9-mediated deletion of exons 2–8, effectively removing both the prodomain and catalytic regions required for PCSK9 function. This null background enabled systematic functional mapping of wild-type (WT) PCSK9 and multiple clinically relevant variants representing well-characterized, recurrent, and previously understudied alleles. Functional assays revealed pronounced heterogeneity among variant activities. The classical gain-of-function (GOF) variants D374Y and R496W exhibited robust suppression of LDL uptake, whereas A443T—an infrequently reported and previously uncharacterized variant—demonstrated a loss-of-function (LOF)-like phenotype with significantly enhanced LDL uptake. Additional poorly characterized variants, including V4I, R104C/V114A, and R496W/N425S, displayed varied functional profiles, providing novel mechanistic insights. Surface LDL receptor (LDLR) levels generally correlated with LDL uptake but revealed unique patterns for specific variants. This KO-based rescue system provides a high-resolution framework for mechanistic classification of both established and poorly characterized PCSK9 variants, bridging the gap between genetic discovery and functional interpretation while supporting precision lipid-lowering strategies.",
  "abstract_shown": true,
  "affiliations": [
    "Collaborative Innovation Center for Translation Medical Testing and Application Technology, Department of Medical Technology, Zhangzhou Health Vocational College, Zhangzhou, Fujian, People's Republic of China",
    "Department of Basic Medicine, Zhangzhou Health Vocational College, Zhangzhou, Fujian, People's Republic of China",
    "Department of Science and Technology, Zhangzhou Health Vocational College, Zhangzhou, Fujian, People's Republic of China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hongmei Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Huili Liu"
    },
    {
      "affs": [
        2
      ],
      "name": "Wenxin Xu"
    },
    {
      "name": "Yuanjun Zeng"
    },
    {
      "name": "Pengfei Huang"
    },
    {
      "name": "Jiawang Guo"
    },
    {
      "name": "Binxiang Cai"
    },
    {
      "name": "Yajing Chen"
    },
    {
      "name": "Yanyan Lin"
    },
    {
      "name": "Chunbin Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2g1cs3dv0nd0k.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0345908",
  "fulltext_url": null,
  "id": "2g1cs3dv0nd0k",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0345908",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2746|Lipoproteins and Cardiovascular Health"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Lipids/Cholesterol"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Guide RNA"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Protein domains"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ribonucleoproteins"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Artificial gene amplification and extension/Polymerase chain reaction"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Cloning"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection"
    ],
    [
      "plos",
      "/Research and analysis methods/Molecular biology techniques/Artificial gene amplification and extension/Polymerase chain reaction"
    ],
    [
      "plos",
      "/Research and analysis methods/Molecular biology techniques/Cloning"
    ],
    [
      "plos",
      "/Research and analysis methods/Molecular biology techniques/Transfection"
    ],
    [
      "plos",
      "/Research and analysis methods/Spectrum analysis techniques/Spectrophotometry/Cytophotometry/Flow cytometry"
    ]
  ],
  "openalex": "W7223669622",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0345908&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/2g1cs3dv0nd0k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.1371/journal.pone.0345908",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0345908"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:molecular biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Functional impact of PCSK9 variants on LDL uptake in a knockout hepatic model",
  "title_text": "Functional impact of PCSK9 variants on LDL uptake in a knockout hepatic model",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:17Z",
  "url": "https://research.draconitic.com/paper/2g1cs3dv0nd0k",
  "venue": "PLOS One",
  "versions": []
}