Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man

doi:10.1084/jem.184.5.1975

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Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man

M Santos, MW Schilham, LH Rademakers, JJ Marx, M de Sousa and H Clevers
Department of Immunology, Eijkman-Winkler Institute, Utrecht, The Netherlands.

Previously, hepatic iron overload resembling that in hereditary hemachromatosis (HH) has been found in beta 2-microglobulin knockout (beta 2m-/-) mice. We have now characterized iron metabolism in beta 2m- /- mice. The mutant mice fail to limit the transfer of iron from mucosal cells into the plasma. Transferrin saturation is abnormally high. Pathologic iron depositions occur predominantly in liver parenchymal cells. Reconstitution with normal hematopoietic cells redistributes the iron from parenchymal to Kupffer cells, but does not correct the mucosal defect. We conclude that (a) iron metabolism is defective in the gut mucosa as well as the liver of beta 2m-/- mice; and (b) a beta 2m-dependent gene product is involved in iron homeostasis. Recently, a novel gene of the major histocompatibility complex class I family, HLA-H, has been found to be mutated in a large proportion of HH patients. Our data provide functional support for the proposed causative role of HLA-H mutations in HH.
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Makui, H., Soares, R. J., Jiang, W., Constante, M., Santos, M. M. (2005). Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading. Blood 106: 2189-2195 [Abstract] [Full Text]
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Pietrangelo, A. (2002). Physiology of iron transport and the hemochromatosis gene. Am. J. Physiol. Gastrointest. Liver Physiol. 282: G403-G414 [Abstract] [Full Text]
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Car, B. D., Eng, V. M. (2001). Special Considerations in the Evaluation of the Hematology and Hemostasis of Mutant Mice. Vet Pathol 38: 20-30 [Abstract] [Full Text]
Roy, C. N., Enns, C. A. (2000). Iron homeostasis: new tales from the crypt. Blood 96: 4020-4027 [Abstract] [Full Text]
Santos, M. M., de Sousa, M., Rademakers, L. H. P. M., Clevers, H., Marx, J. J. M., Schilham, M. W. (2000). Iron Overload and Heart Fibrosis in Mice Deficient for Both {beta}2-Microglobulin and Rag1. Am. J. Pathol. 157: 1883-1892 [Abstract] [Full Text]
Tolosano, E., Hirsch, E., Patrucco, E., Camaschella, C., Navone, R., Silengo, L., Altruda, F. (1999). Defective Recovery and Severe Renal Damage After Acute Hemolysis in Hemopexin-Deficient Mice. Blood 94: 3906-3914 [Abstract] [Full Text]
Bahram, S., Gilfillan, S., Kuhn, L. C., Moret, R., Schulze, J. B., Lebeau, A., Schumann, K. (1999). Experimental hemochromatosis due to MHC class I HFE deficiency: Immune status and iron metabolism. Proc. Natl. Acad. Sci. USA 96: 13312-13317 [Abstract] [Full Text]
Roest, M., van der Schouw, Y. T., de Valk, B., Marx, J. J. M., Tempelman, M. J., de Groot, P. G., Sixma, J. J., Banga, J. D. (1999). Heterozygosity for a Hereditary Hemochromatosis Gene Is Associated With Cardiovascular Death in Women. Circulation 100: 1268-1273 [Abstract] [Full Text]
de Valk, B., Marx, J. J. M. (1999). Iron, Atherosclerosis, and Ischemic Heart Disease. Arch Intern Med 159: 1542-1548 [Abstract] [Full Text]
Walker, A. P, Wallace, D. F, Partridge, J., Bomford, A. B, Dooley, J. S (1999). Atypical haemochromatosis: phenotypic spectrum and beta 2-microglobulin candidate gene analysis. J. Med. Genet. 36: 537-541 [Abstract] [Full Text]
Han, O., Fleet, J. C., Wood, R. J. (1999). Reciprocal Regulation of HFE and Nramp2 Gene Expression by Iron in Human Intestinal Cells. J. Nutr. 129: 98-104 [Abstract] [Full Text]
Yu, J., Yu, Z. K., Wessling-Resnick, M. (1998). Expression of SFT (Stimulator of Fe Transport) Is Enhanced by Iron Chelation in HeLa Cells and by Hemochromatosis in Liver. J. Biol. Chem. 273: 34675-34678 [Abstract] [Full Text]
Santos, M., Clevers, H., de Sousa, M., Marx, J.J.M. (1998). Adaptive Response of Iron Absorption to Anemia, Increased Erythropoiesis, Iron Deficiency, and Iron Loading in beta 2-Microglobulin Knockout Mice. Blood 91: 3059-3065 [Abstract] [Full Text]
Recalcati, S., Pometta, R., Levi, S., Conte, D., Cairo, G. (1998). Response of Monocyte Iron Regulatory Protein Activity to Inflammation: Abnormal Behavior in Genetic Hemochromatosis. Blood 91: 2565-2572 [Abstract] [Full Text]
Zhou, X. Y., Tomatsu, S., Fleming, R. E., Parkkila, S., Waheed, A., Jiang, J., Fei, Y., Brunt, E. M., Ruddy, D. A., Prass, C. E., Schatzman, R. C., O'Neill, R., Britton, R. S., Bacon, B. R., Sly, W. S. (1998). HFE gene knockout produces mouse model of hereditary�hemochromatosis. Proc. Natl. Acad. Sci. USA 95: 2492-2497 [Abstract] [Full Text]
Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., Schatzman, R. C., Britton, R. S., Bacon, B. R., Sly, W. S. (1997). Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with beta 2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7�cells. Proc. Natl. Acad. Sci. USA 94: 12384-12389 [Abstract] [Full Text]
Feder, J. N., Tsuchihashi, Z., Irrinki, A., Lee, V. K., Mapa, F. A., Morikang, E., Prass, C. E., Starnes, S. M., Wolff, R. K., Parkkila, S., Sly, W. S., Schatzman, R. C. (1997). The Hemochromatosis Founder Mutation in HLA-H Disrupts beta 2-Microglobulin Interaction and Cell Surface Expression. J. Biol. Chem. 272: 14025-14028 [Abstract] [Full Text]
Santos, M., Clevers, H. C., Marx, J. J.M. (1997). Mutations of the Hereditary Hemochromatosis Candidate Gene HLA-H in Porphyria Cutanea Tarda. NEJM 336: 1327-1328 [Full Text]
Waheed, A., Grubb, J. H., Zhou, X. Y., Tomatsu, S., Fleming, R. E., Costaldi, M. E., Britton, R. S., Bacon, B. R., Sly, W. S. (2002). Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc. Natl. Acad. Sci. USA 99: 3117-3122 [Abstract] [Full Text]
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