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 hereditary diseases. A phenotypic hallmark of HC is low iron in reticuloendothelial cells in spite of body iron overload. Most patients with HC have the same mutation, a change of cysteine at position 282 to tyrosine (C282Y) in the HFE protein. The role of HFE in iron metabolism and the basis for the phenotypic abnormalities of HC are not understood. To clarify the role of HFE in the phenotypic expression of HC, we studied monocytes-macrophages from subjects carrying the C282Y mutation in the HFE protein and clinically expressing HC and transfected them with wild-type HFE by using an attenuated Salmonella typhimurium strain as a gene carrier. The Salmonella system allowed us to deliver genes of interest specifically to monocytes-macrophages with high transduction efficiency. The accumulation of (55)Fe delivered by (55)Fe-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 (55)Fe delivered by (55)Fe-Tf was raised by 40% to 60%, and this was reflected by an increase in the (55)Fe-ferritin pool within the HFE-transfected cells. These results suggest that the iron-deficient 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.
Montosi
G
G
Unit for the Study of Disorders of Iron Metabolism, Department of Internal Medicine, University of Modena and Reggio Emilia, Italy.
Paglia
P
P
Garuti
C
C
Guzman
C A
CA
Bastin
J M
JM
Colombo
M P
MP
Pietrangelo
A
A
D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism*; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins; D009000:Monocytes / Q000378:metabolism*; D012486:Salmonella typhimurium; D014168:Transferrin / Q000378:metabolism
C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D007501:Iron