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

TLDR

Hemochromatosis is a progressive iron overload disorder common in Europeans, typically autosomal‑recessive and linked to HFE missense mutations, with ferroportin (SLC11A3) located in a candidate interval identified by strong lod scores. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation. A large pedigree study identified autosomal‑dominant hemochromatosis mapping to 2q32, associated with a nonconservative A77D missense mutation in ferroportin that is absent in 100 controls and linked to early iron accumulation in reticuloendothelial cells.

Abstract

Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.