Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene

Hemochromatosis is a progressive iron overload disorder that is prevalent a mong individuals of European descent. It is usually inherited in an autosom al-recessive pattern and associated with missense mutations in HFE, an atyp ical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distin guished by early iron accumulation in reticuloendothelial cells. Through an alysis of a large pedigree, we have determined that this disease maps to 2q 32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export pr otein, lies within a candidate interval defined by highly significant lod s cores. We show that the iron-loading phenotype in autosomal-dominant hemoch romatosis is associated with a nonconservative missense mutation in the fer roportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control i ndividuals. We propose that partial loss of ferroportin function leads to a n imbalance in iron distribution and a consequent increase in tissue iron a ccumulation.