Impaired Iron Transport Activity of Ferroportin 1 in Hereditary Iron Overload

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Abstract
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 V162Δ) were all expressed at the plasma membrane at similar levels. All mutations caused significant reductions in 59Fe efflux compared to wild type but all retained some residual transport activity. A77D had the strongest effect on 59Fe efflux (remaining activity 9% of wild-type control), whereas the N144H mutation retained the highest efflux activity (42% of control). The Q248H and V162Δ 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.