Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis

Martina Muckenthaler, Cindy N. Roy, Ángel O. Custodio, Belén Miñana, Jos DeGraaf, Lynne K. Montross, Nancy C. Andrews, Matthias W. Hentze

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Abstract

Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption. 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 function. 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 contradictory. 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.

Original languageEnglish (US)
Pages (from-to)102-107
Number of pages6
JournalNature genetics
Volume34
Issue number1
DOIs
StatePublished - May 1 2003

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ASJC Scopus subject areas

  • Genetics

Cite this

Muckenthaler, M., Roy, C. N., Custodio, Á. O., Miñana, B., DeGraaf, J., Montross, L. K., Andrews, N. C., & Hentze, M. W. (2003). Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nature genetics, 34(1), 102-107. https://doi.org/10.1038/ng1152