Genes that modify the hemochromatosis phenotype in mice

Hereditary hemochromatosis (HH) is a prevalent human disease caused by a mu tation in HFE, which encodes an atypical HLA class I protein involved in re gulation of intestinal iron absorption. To gain insight into the pathogenes is of hemochromatosis, we have bred Hfe knockout mice to strains carrying o ther mutations that impair normal iron metabolism. Compound mutant mice lac king both Hfe and its interacting protein, beta-2 microglobulin (B2m), depo sit more tissue iron than mice lacking Hfe only, suggesting that another B2 m-interacting protein may be involved in iron regulation. Hfe knockout mice carrying mutations in the iron transporter DMT1 fail to load iron, indicat ing that hemochromatosis involves iron flux through DMT1. Similarly, compou nd mutants deficient: in both Hfe and hephaestin (Heph) show less iron load ing than do Hfe knockout mice, indicating that iron absorption in hemochrom atosis involves the function of Heph as well. Finally, compound mutants lac king Hfe and the transferrin receptor accumulate more tissue iron than do m ice lacking Hfe alone, consistent with the idea that interaction between th ese two proteins contributes to the control of normal iron absorption. In a ddition to providing insight into the pathogenesis of HH, our results sugge st that each of these genes might be a candidate modifier of the human hemo chromatosis phenotype.