{
  "abstract": "Background & aims\n\nHyperferritinemia frequently remains unexplained despite comprehensive evaluation. We conducted a sequencing-based exome association study to identify genetic variants associated with plasma ferritin levels in patients with unexplained hyperferritinemia.Methods\n\nGene-based association testing using the combined multivariate and collapsing method with Bayesian inference was performed in patients referred for clinical exome sequencing (n = 392) after excluding known causes of hyperferritinemia. Findings were validated in an independent replication cohort (n = 263). Functional studies included Muc13 knockout mice, intestinal cell models, proteomic analysis, and site-directed mutagenesis.Results\n\nThe MUC13 p.Arg503Ser variant showed extreme Bayesian evidence for association with increased plasma ferritin, iron, and transferrin saturation in the homozygous state. In the replication cohort, the homozygous 503Ser genotype was the strongest independent predictor of elevated transferrin saturation (odds ratio, 4.52; 95% CI, 1.55-13.19; p = 0.006). Conversely, Muc13 knockout mice exhibited lower plasma iron and transferrin saturation, consistent with a role for MUC13 in intestinal iron absorption. In human intestinal cells, MUC13 knockdown reduced ferric iron uptake, whereas MUC13 overexpression increased it. Proteomic analysis identified integrin alpha 6 and integrin beta 4 as MUC13-associated candidates. Cells expressing the homozygous 503Ser variant showed higher cell surface MUC13 expression and increased ferritin heavy chain 1, calreticulin, and nuclear factor erythroid 2-related factor 2 levels after iron exposure.Conclusions\n\nThese findings support a role for MUC13 in intestinal ferric iron absorption and a causal link between the MUC13 homozygous 503Ser genotype and enhanced cellular iron uptake, which could contribute to a better understanding of unexplained hyperferritinemia.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Genomic Medicine, Division of Biochemistry, Molecular Biology and Nutrition, University Hospital of Nancy, Nancy, France.",
    "QIMR Berghofer Medical Research Institute, Cancer Program, Herston, Queensland, Australia.",
    "Cancer Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.",
    "University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, Nancy, France.",
    "Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, Nancy, France.",
    "Department of Gastroenterology and Liver Diseases, University Hospital of Nancy, Nancy, France.",
    "Department of Pathology, University Hospital of Nancy, Nancy, France.",
    "Proteomics Core Facility, Translational Research Institute, Woolloongabba, Australia.",
    "Centre de Recherches sur l'Inflammation, INSERM U1149, Université Paris Cité, Paris, France.",
    "Laboratory of Biochemistry, Beaujon University Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.",
    "Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France.",
    "Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.",
    "Faculty of Medicine, Dentistry and Health Sciences, the University of Melbourne, Parkville, Victoria, Australia.",
    "Joan Klein Jacobs Center for Precision Nutrition and Health, Cornell University, Ithaca, New York, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 23,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jonas Callet",
      "orcid": "0009-0007-2406-2694"
    },
    {
      "affs": [
        1
      ],
      "name": "Yong H Sheng"
    },
    {
      "affs": [
        2
      ],
      "name": "Yaowu He"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Maël Silva Rodriguez",
      "orcid": "0009-0007-6191-7452"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Céline Chéry"
    },
    {
      "affs": [
        3
      ],
      "name": "Ramia Safar"
    },
    {
      "affs": [
        0
      ],
      "name": "Françoise Barbé"
    },
    {
      "affs": [
        5
      ],
      "name": "Mouni Bensenane",
      "orcid": "0000-0003-1896-1304"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Rosa-Maria Guéant-Rodriguez",
      "orcid": "0000-0003-1402-3716"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Fares Namour",
      "orcid": "0000-0002-9267-4701"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Guillaume Gauchotte"
    },
    {
      "affs": [
        7
      ],
      "name": "Janelle Louise Hancock"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Hana Manceau",
      "orcid": "0000-0003-4158-0964"
    },
    {
      "affs": [
        8,
        10
      ],
      "name": "Thibaud Lefebvre"
    },
    {
      "affs": [
        8
      ],
      "name": "Dimitri Tchernitchko",
      "orcid": "0000-0001-9820-0374"
    },
    {
      "affs": [
        8,
        10
      ],
      "name": "Hervé Puy"
    },
    {
      "affs": [
        11
      ],
      "name": "Timothy H Florin"
    },
    {
      "affs": [
        11
      ],
      "name": "Jakob Begun",
      "orcid": "0000-0001-5256-7672"
    },
    {
      "affs": [
        2
      ],
      "name": "John D Hooper",
      "orcid": "0000-0003-1054-8486"
    },
    {
      "affs": [
        3,
        5
      ],
      "name": "Jean-Pierre Bronowicki",
      "orcid": "0000-0003-1631-500X"
    },
    {
      "affs": [
        1,
        12
      ],
      "name": "Michael A McGuckin",
      "orcid": "0000-0002-8375-2675"
    },
    {
      "affs": [
        13
      ],
      "name": "Jean-Louis Guéant",
      "orcid": "0000-0002-5067-042X"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Abderrahim Oussalah",
      "orcid": "0000-0002-9731-4529"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9ek7jxy6j80mw.bib",
  "cited_by": 0,
  "doi": "10.1111/liv.70901",
  "fulltext_url": "https://europepmc.org/articles/PMC13702042",
  "id": "9ek7jxy6j80mw",
  "issns": [
    "1478-3223",
    "1478-3231"
  ],
  "landing_url": "https://europepmc.org/article/MED/42929734",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2720|Iron Metabolism and Disorders"
    ]
  ],
  "openalex": "W7223658495",
  "pdf_url": "https://europepmc.org/articles/PMC13702042?pdf=render",
  "pmcid": "PMC13702042",
  "pmid": "42929734",
  "published": "2026-10-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9ek7jxy6j80mw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:51Z",
      "native_id": "MED:42929734",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42929734"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Iron Metabolism and Disorders",
      "subfield": "general"
    }
  ],
  "title": "A MUC13 Variant Enhances Intestinal Ferric Iron Absorption in Unexplained Hyperferritinemia.",
  "title_text": "A MUC13 Variant Enhances Intestinal Ferric Iron Absorption in Unexplained Hyperferritinemia.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:51Z",
  "url": "https://research.draconitic.com/paper/9ek7jxy6j80mw",
  "venue": "Liver international : official journal of the International Association for the Study of the Liver",
  "versions": []
}