A MUC13 Variant Enhances Intestinal Ferric Iron Absorption in Unexplained Hyperferritinemia.
14 affiliations
- 1Department of Genomic Medicine, Division of Biochemistry, Molecular Biology and Nutrition, University Hospital of Nancy, Nancy, France.
- 2QIMR Berghofer Medical Research Institute, Cancer Program, Herston, Queensland, Australia.
- 3Cancer Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
- 4University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, Nancy, France.
- 5Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, Nancy, France.
- 6Department of Gastroenterology and Liver Diseases, University Hospital of Nancy, Nancy, France.
- 7Department of Pathology, University Hospital of Nancy, Nancy, France.
- 8Proteomics Core Facility, Translational Research Institute, Woolloongabba, Australia.
- 9Centre de Recherches sur l'Inflammation, INSERM U1149, Université Paris Cité, Paris, France.
- 10Laboratory of Biochemistry, Beaujon University Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
- 11Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France.
- 12Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
- 13Faculty of Medicine, Dentistry and Health Sciences, the University of Melbourne, Parkville, Victoria, Australia.
- 14Joan Klein Jacobs Center for Precision Nutrition and Health, Cornell University, Ithaca, New York, USA.
Abstract
Background & aims
Hyperferritinemia 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
Gene-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
The 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
These 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.
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BibTeX
@article{callet2026muc13,
title = {{A MUC13 Variant Enhances Intestinal Ferric Iron Absorption in Unexplained Hyperferritinemia.}},
author = {Jonas Callet and Yong H Sheng and Yaowu He and Maël Silva Rodriguez and Céline Chéry and Ramia Safar and Françoise Barbé and Mouni Bensenane and Rosa-Maria Guéant-Rodriguez and Fares Namour and Guillaume Gauchotte and Janelle Louise Hancock and Hana Manceau and Thibaud Lefebvre and Dimitri Tchernitchko and Hervé Puy and Timothy H Florin and Jakob Begun and John D Hooper and Jean-Pierre Bronowicki and Michael A McGuckin and Jean-Louis Guéant and Abderrahim Oussalah},
journal = {Liver international : official journal of the International Association for the Study of the Liver},
year = {2026},
month = oct,
doi = {10.1111/liv.70901},
url = {https://europepmc.org/article/MED/42929734},
note = {CC BY},
}
RIS
TY - JOUR
TI - A MUC13 Variant Enhances Intestinal Ferric Iron Absorption in Unexplained Hyperferritinemia.
AU - Jonas Callet
AU - Yong H Sheng
AU - Yaowu He
AU - Maël Silva Rodriguez
AU - Céline Chéry
AU - Ramia Safar
AU - Françoise Barbé
AU - Mouni Bensenane
AU - Rosa-Maria Guéant-Rodriguez
AU - Fares Namour
AU - Guillaume Gauchotte
AU - Janelle Louise Hancock
AU - Hana Manceau
AU - Thibaud Lefebvre
AU - Dimitri Tchernitchko
AU - Hervé Puy
AU - Timothy H Florin
AU - Jakob Begun
AU - John D Hooper
AU - Jean-Pierre Bronowicki
AU - Michael A McGuckin
AU - Jean-Louis Guéant
AU - Abderrahim Oussalah
PY - 2026
DA - 2026/10/30
JO - Liver international : official journal of the International Association for the Study of the Liver
DO - 10.1111/liv.70901
UR - https://europepmc.org/article/MED/42929734
AB - Background & aims Hyperferritinemia 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 Gene-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 The 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 These 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.
SN - 1478-3223
SN - 1478-3231
ER -