A MUC13 Variant Enhances Intestinal Ferric Iron Absorption in Unexplained Hyperferritinemia

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.

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.

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.

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.