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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1125-1129
Wild-type HFE protein normalizes transferrin iron accumulation in
macrophages from subjects with hereditary hemochromatosis
Giuliana Montosi,
Paola Paglia,
Cinzia Garuti,
Carlos A. Guzman,
Judy M. Bastin,
Mario P. Colombo, and
Antonello Pietrangelo
From the Unit for the Study of Disorders of Iron Metabolism,
Department of Internal Medicine, University of Modena and Reggio
Emilia, Modena; Immunotherapy and Gene Therapy Unit, Istituto Nazionale
Tumori, Milano, Italy; Division of Microbiology, GBF-National Research
Center for Biotechnology, Braunschweig, Germany; Institute of Molecular
Medicine, Oxford University, John Radcliffe Hospital, Oxford, United
Kingdom.
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 55Fe delivered by
55Fe-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 55Fe delivered by 55Fe-Tf was
raised by 40% to 60%, and this was reflected by an increase in the
55Fe-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.
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