Abstract
Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption1,2. Most cases arise from a founder mutation in HFE (845G→A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with β2-microglobulin. Mice homozygous with respect to a null allele of Hfe (Hfe−/−) or homozygous with respect to the orthologous 882G→A mutation (Hfe845A/845A) develop iron overload that recapitulates hereditary hemochromatosis in humans, confirming that hereditary hemochromatosis arises from loss of HFE function3. Much work has focused on an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells is thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (also called DMT1, DCT1 and NRAMP2) and SLC11A3 (also called IREG1, ferroportin and MTP1; ref. 3). Published data on the expression of these transporters in the duodenum of HFE-deficient mice and humans are contradictory4,5,6,7,8. In this report, we used a custom microarray to assay changes in duodenal and hepatic gene expression in Hfe-deficient mice. We found unexpected alterations in the expression of Slc39a1 (mouse ortholog of SLC11A3) and Cybrd1, which encode key iron transport proteins, and Hamp (hepcidin antimicrobial peptide), a hepatic regulator of iron transport. We propose that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.
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Acknowledgements
We thank A. Richter and W. Ansorge for support in setting up the IronChip microarray platform; V. Benes, R. Carmouche and M. Benesova for maintaining it; numerous colleagues who contributed cDNA clones; and U. Ringeisen for support with art work. We acknowledge the Resource Center and Primary Database for the supply of cDNA clones. M.W.H. acknowledges funds from the Gottfried Wilhelm Leibniz Prize. N.C.A. is an Associate Investigator of the Howard Hughes Medical Institute. C.N.R. was funded by a training grant from the US National Institutes of Health.
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Muckenthaler, M., Roy, C., Custodio, Á. et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 34, 102–107 (2003). https://doi.org/10.1038/ng1152
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DOI: https://doi.org/10.1038/ng1152
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