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Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse

Abstract

Iron is essential for many cellular functions; consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. Despite the clinical prevalence of these disorders, the mechanism by which dietary iron is absorbed into the body is poorly understood. We have identified a key component in intestinal iron transport by study of the sex–linked anaemia (sla) mouse, which has a block in intestinal iron transport1. Mice carrying the sla mutation develop moderate to severe microcytic hypochromic anaemia1. Although these mice take up iron from the intestinal lumen into mature epithelial cells normally2, the subsequent exit of iron into the circulation is diminished3. As a result, iron accumulates in enterocytes and is lost during turnover of the intestinal epithelium4. Biochemical studies have failed to identify the underlying difference between sla and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe here a novel gene, Heph, encoding a transmembrane–bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multi–copper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.

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Figure 1: Mapping of the sla locus.
Figure 2: Comparison of mouse ceruloplasmin– and hephaestin–derived amino acid sequences.
Figure 3: Expression of Heph in wild–type mice.
Figure 4: Analysis of Heph in sla mice.
Figure 5: Schematic depiction of the partial genomic deletion of Heph in sla animals.

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Acknowledgements

We thank N. Brockdorff and E. Tuddenham for assaying the sla animals; M. Gunthorpe and J. DeYoung for DNA synthesis and sequencing; M. Schueler and H. Willard for communicating unpublished results; and M. Fleming and N. Andrews for unpublished sla mapping data. J.G. is an associate investigator with the Howard Hughes Medical Institute. This work was supported in part by a grant from the National Health and Medical Research Council of Australia to G.J.A. and by a grant from the National Institutes of Health to J.G.

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Correspondence to Jane Gitschier.

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Vulpe, C., Kuo, YM., Murphy, T. et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21, 195–199 (1999). https://doi.org/10.1038/5979

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