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

Iron is essential for many cellular functions; consequently, disturbances o f 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 (s/a) mouse, which has a block in intestinal iron transport(1). Mice carrying the sla mutation deve lop moderate to severe microcytic hypochromic anaemia(1). Although these mi ce take up iron from the intestinal lumen into mature epithelial cells norm ally(2), the subsequent exit of iron into the circulation is diminished(3). As a result, iron accumulates in enterocytes and is lost during turnover o f the intestinal epithelium(4). Biochemical studies have failed to identify the underlying difference between s/a and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe her e a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologu e that is mutant in the sla mouse and highly expressed in intestine. We sug gest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it i s an important link between copper and iron metabolism in mammals.