HFE GENE KNOCKOUT PRODUCES MOUSE MODEL OF HEREDITARY HEMOCHROMATOSIS

Hereditary hemochromatosis (HH) is a common autosomal recessive diseas e characterized by increased iron absorption and progressive iron stor age that results in damage to major organs in the body. Recently, a ca ndidate gene for KH called HFE encoding a major histocompatibility com plex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that th e HFE gene Is involved in regulation of iron homeostasis, we studied t he effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameter s of iron homeostasis. Even on a standard diet, by 10 weeks of age, fa sting transferrin saturation was significantly elevated compared with normal littermates (96 +/- 5% vs. 77 +/- 3%, P < 0.007), and hepatic i ron concentration was 8-fold higher than that of wild-type littermates (2,071 +/- 450 vs. 255 +/- 23 mu g/g dry wt, P < 0.002). Stainable he patic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and k idney were not significantly different. Erythroid parameters were norm al, indicating that the anemia did not contribute to the increased iro n storage. This study shows that the HFE protein is involved in the re gulation of iron homeostasis and that mutations in this gene are respo nsible for M. The knockout mouse model of HI-I will facilitate investi gation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for preventio n or correction of iron overload.