Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis

Hereditary hemochromatosis (HC) is one of the most common single-gene hered itary diseases. A phenotypic hallmark of HC is low iron in reticuloendothel ial cells in spite of body iron overload. Most patients with HC have the sa me mutation, a change of cysteine at position 282 to tyrosine (C282Y) in th e HFE protein. The role of HFE in iron metabolism and the basis for the phe notypic abnormalities of HC are not understood. To clarify the role of HFE in the phenotypic expression of HC, we stud led monocytes-macrophages from subjects carrying the C282Y mutation in the HFE protein and clinically expr essing HC and transfected them with wild-type HFE by using an attenuated Sa lmonella typhimurium strain as a gene carrier. The Salmonella system allowe d us to deliver genes of interest specifically to monocytes-macrophages wit h high transduction efficiency. The accumulation of Fe-55 delivered by Fe-5 5-Tf was significantly lower in macrophages from patients with HC than from controls expressing wild-type HFE. Transfection of HC macrophages with the HFE gene resulted in a high level of expression of HFE protein at the cell surface, The accumulation of Fe-55 delivered by 55Fe-Tf was raised by 40% to 60%, and this was reflected by an increase in the Fe-55-ferritin pool wi thin the HFE-transfected cells. These results suggest that the Iron-deficie nt phenotype of HC macrophages is a direct effect of the HFE mutation, and they demonstrate a role for HFE in the accumulation of iron in these cells. (C) 2000 by The American Society of Hematology.