To investigate the functional significance of mutations in Ferroportin that cause hereditary iron overload, we directly measured the iron efflux activity of the proteins expressed in Xenopus oocytes. We found that wild type and mutant Ferroportin molecules (A77D, N144H, Q248H and V162Delta) were all expressed at the plasma membrane at similar levels. All mutations caused significant reductions in (59)Fe efflux compared to wild type but all retained some residual transport activity. A77D had the strongest effect on (59)Fe efflux (remaining activity 9% of wild-type control), whereas the N144H mutation retained the highest efflux activity (42% of control). The Q248H and V162Delta mutations were intermediate between these values. Co-injection of mutant and wild-type mRNAs revealed that the A77D and N144H mutations had a dominant negative effect on the function of the WT protein.

Duodenal cytochrome b (Dcytb) is a haem protein similar to the cytochrome b561 protein family. Dcytb is highly expressed in duodenal brush-border membrane and is implicated in dietary iron absorption by reducing dietary ferric iron to the ferrous form for transport via Nramp2/DCT1 (divalent-cation transporter 1)/DMT1 (divalent metal-transporter 1). The protein is expressed in other tissues and may account for ferric reductase activity at other sites in the body.

Fe homeostasis is maintained by regulation of Fe absorption to balance largely unregulated body Fe losses. The majority of human subjects maintain relatively constant Fe stores; however, Fe deficiency and Fe overload are common conditions. Fe overload is frequently associated with mutations in genes of Fe metabolism. The present paper summarises present knowledge of these mutations as well as indicating other genes that animal studies have implicated as candidates for influencing body Fe stores.