Mutations in the SLC40A1 gene, which encodes ferroportin, are associated with 
autosomal dominant hemochromatosis. Ferroportin is inhibited directly by 
hepcidin, a key iron-regulatory peptide, and functional consequences of SLC40A1 
mutations account for observed phenotypic differences in patients with 
ferroportin disease. We describe a large pedigree with a novel SLC40A1 mutation 
and, through in vitro analysis, elucidate the associated molecular mechanism of 
iron overload. The entire coding sequence of the SLC40A1 gene was sequenced in a 
pedigree, presenting with autosomal dominant hyperferritinemia. The functional 
effects of a novel SLC40A1 mutation were studied by overexpression of wild-type 
and mutant ferroportin fusion proteins in human embryonic kidney cells. Iron 
export was studied in these cells using (59)Fe transport assays; subcellular 
localization of ferroportin was examined by way of confocal microscopy. A novel 
SLC40A1 mutation p.R489K segregated with iron overload in a family with clinical 
and histopathological signs of macrophage-type ferroportin disease. Human 
embryonic kidney cells overexpressing p.R489K ferroportin showed decreased iron 
export capacity when compared with wild-type ferroportin overexpressing cells. 
Subcellular localization studies demonstrated that p.R489K ferroportin was 
retained abnormally within an intracellular compartment.
CONCLUSION: We report a novel pathological SLC40A1 variant associated with 
abnormal cell surface expression of ferroportin due to intracellular retention 
of the mutant protein. These findings predict macrophage-type ferroportin 
disease, the phenotype observed in this kindred. Study of the molecular cell 
biology of ferroportin and its mutants is key to understanding the pathogenesis 
of this increasingly recognized form of hemochromatosis, which responds poorly 
to conventional therapy.