title: Genes that modify the hemochromatosis phenotype in mice.
abstract: Hereditary hemochromatosis (HH) is a prevalent human disease caused by a mutation in HFE, which encodes an atypical HLA class I protein involved in regulation of intestinal iron absorption. To gain insight into the pathogenesis of hemochromatosis, we have bred Hfe knockout mice to strains carrying other mutations that impair normal iron metabolism. Compound mutant mice lacking both Hfe and its interacting protein, beta-2 microglobulin (B2m), deposit more tissue iron than mice lacking Hfe only, suggesting that another B2m-interacting protein may be involved in iron regulation. Hfe knockout mice carrying mutations in the iron transporter DMT1 fail to load iron, indicating that hemochromatosis involves iron flux through DMT1. Similarly, compound mutants deficient in both Hfe and hephaestin (Heph) show less iron loading than do Hfe knockout mice, indicating that iron absorption in hemochromatosis involves the function of Heph as well. Finally, compound mutants lacking Hfe and the transferrin receptor accumulate more tissue iron than do mice lacking Hfe alone, consistent with the idea that interaction between these two proteins contributes to the control of normal iron absorption. In addition to providing insight into the pathogenesis of HH, our results suggest that each of these genes might be a candidate modifier of the human hemochromatosis phenotype.
authors.affiliation: Division of Hematology-Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Levy
authors.forename: L K
authors.initials: LK
authors.lastname: Montross
authors.forename: N C
authors.initials: NC
authors.lastname: Andrews
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006706:Homeostasis; D007408:Intestinal Absorption; D019266:Iron, Dietary / Q000378:metabolism*; D033862:Iron-Binding Proteins; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D011990:Receptors, Transferrin / Q000235:genetics*; D001613:beta 2-Microglobulin / Q000235:genetics*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D019266:Iron, Dietary; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D001613:beta 2-Microglobulin; D000099236:Solute Carrier Family 11, Member 2; C499535:Hfe protein, mouse