Impaired iron transport activity of ferroportin 1 in hereditary iron overload

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 V162 Delta) were all expressed at the plasma membrane at similar levels. All mutations caused significant reductions in Fe-59 efflux compared to wild type but all retained some residual transport activity. A77D had the strongest effect on Fe-59 efflux (remaining activity 9% of wildtype control), whereas the N144H mutation retained the highest efflux activity (42% of control). The Q248H and V162 Delta mutations were intermediate between these values. Co-injection of mutant and wildtype mRNAs revealed that the A77D and N144H mutations had a dominant negative effect on the function of the WT protein.