GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS

描述：遗传性血色病（HH）是一种非常常见的常染色体 一种隐性疾病，其中铁吸收增加导致铁中毒 沉积在各种器官中，导致肝硬化，肝细胞癌， 糖尿病心力衰竭关节炎和阳痿 一种MHC I类分子 一个叫做HLA-H的候选基因已经被确认。 近90%的HH 患者是相同突变（C282 Y）的纯合子，或复合突变 HLA-H中C282 Y和H63 D突变的杂合子。 其他研究 也间接牵连MHC I类蛋白在铁代谢，但 铁吸收的实际机制以及HLA-H如何调节铁吸收， 未知 这项研究的主要目标是了解HLA-H的功能， 基因产物，并测试该基因中的C282 Y突变的假设， 是HH的分子基础。 五个具体目标是：1）表征 HH突变对HLA-H基因特性的影响 在转染的COS细胞中表达产物。 2)纯化正常和突变体 HLA-H蛋白并鉴定其配体和其他相互作用蛋白。 3)使用免疫组织化学证明HH突变对 HLA-H蛋白在组织中的细胞和亚细胞定位 HH患者。 4)确定铁负荷的影响，以及 已知增加铁吸收的小鼠突变， HLA-H基因产物在小鼠中的表达和定位。 第五章） 通过靶向基因破坏HH基因产生HH敲除小鼠模型。 HLA-H基因 各种生物化学、分子、细胞生物学和 这些研究将采用免疫学技术， 现代小鼠遗传学的优势。 预计， HLA-H基因产物在铁稳态调节中的作用将得以确立 以及这两种蛋白质突变的机制 对HH的贡献将被定义。 这些研究不仅可以改善我们的 了解铁的吸收是如何正常调节的，但也可能 提出了治疗铁吸收过度紊乱的新策略。

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.