Levy J E, Montross L K, Andrews N C
Division of Hematology-Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
J Clin Invest. 2000 May;105(9):1209-16. doi: 10.1172/JCI9635.
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.
遗传性血色素沉着症（HH）是一种常见的人类疾病，由HFE基因突变引起，该基因编码一种参与调节肠道铁吸收的非典型HLA I类蛋白。为了深入了解血色素沉着症的发病机制，我们将Hfe基因敲除小鼠与携带其他损害正常铁代谢突变的品系进行杂交。缺乏Hfe及其相互作用蛋白β2微球蛋白（B2m）的复合突变小鼠比仅缺乏Hfe的小鼠沉积更多的组织铁，这表明另一种与B2m相互作用的蛋白可能参与铁调节。携带铁转运蛋白DMT1突变的Hfe基因敲除小鼠无法加载铁，这表明血色素沉着症涉及通过DMT1的铁通量。同样，缺乏Hfe和亚铁氧化酶（Heph）的复合突变体比Hfe基因敲除小鼠显示出更少的铁负载，这表明血色素沉着症中的铁吸收也涉及Heph的功能。最后，缺乏Hfe和转铁蛋白受体的复合突变体比仅缺乏Hfe的小鼠积累更多的组织铁，这与这两种蛋白之间的相互作用有助于控制正常铁吸收的观点一致。除了深入了解HH的发病机制外，我们的结果表明，这些基因中的每一个都可能是人类血色素沉着症表型的候选修饰基因。
