GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS

点击翻译按钮获取中文摘要

DESCRIPTION: Hereditary hemochromatosis (HH) is a very common autosomal recessive disorder in which increased iron absorption leads to toxic iron deposits in a variety of organs causing cirrhosis, hepatocellular cancer, diabetes, heart failure, arthritis, and impotence. An MHC class I-like candidate gene, called HLA-H, has been identified. Nearly 90% of HH patients are homozygous for the same mutation (C282Y), or compound heterozygotes for C282Y and H63D mutations in HLA-H. Other studies have also indirectly implicated MHC class I-like proteins in iron metabolism, but the actual mechanism of iron absorption and how HLA-H could regulate it are unknown. The broad goals of this research are to understand the function of the HLA-H gene product and to test the hypothesis that the C282Y mutation in this gene is the molecular basis for HH. The five specific aims are: 1) Characterize the effects of the HH mutation(s) on the properties of the HLA-H gene product expressed in transfected COS cells. 2) Purify normal and mutant HLA-H proteins and identify their ligand(s) and other interacting proteins. 3) Use immunohistochemistry to demonstrate the effects of HH mutations(s) on the cellular and subcellular localization of the HLA-H protein in tissues of HH patients. 4) Determine the effects of iron loading, and the effects of mouse mutations known to increase iron absorption, on the level of expression and the localization of the HLA-H gene product in mice. 5) Produce a knockout mouse model for HH by targeted gene disruption of the HLA-H gene. A variety of biochemical, molecular, cell biological, and immunological techniques will be employed for these studies which also take advantage of modern mouse genetics. It is expected that a role for the HLA-H gene product in the regulation of iron homeostasis will be established and the mechanisms by which the two described mutations in this protein contribute to HH will be defined. These studies will not only improve our understanding of how iron absorption is normally regulated, but may also suggest new strategies for treating disorders of excessive iron absorption.