Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with beta(2)-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells
Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with beta(2)-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells
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DOI：
10.1073/pnas.94.23.12384
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发表时间：
1997-11-11
影响因子：
11.1
通讯作者：
Sly, WS
中科院分区：
文献类型：
--
作者：
Waheed, A;Parkkila, S;Sly, WS
遗传性血色素沉着症（HH）是人类最常见的常染色体隐性遗传病，最近克隆了一个HFE候选基因，编码主要组织相容性复合体I家族的一个新成员。大多数HH患者是HFE基因Cys-282 -> Tyr（C282 Y）突变的纯合子，该突变已被证明破坏了与β 2-微球蛋白的相互作用;第二种突变His-63 --> Asp（H63 D）在C282 Y突变杂合的HH患者中富集，本研究的目的是确定C282 Y和H63 D突变对细胞运输和降解的影响HFE蛋白在转染的COS-7细胞中，结果表明，虽然野生型和H63 D HFE蛋白与β（2）-微球蛋白结合并在COS-7细胞的细胞表面上表达，但C282 Y HFE蛋白丧失了这些能力。我们提供的生物化学和免疫荧光数据表明C282 Y突变蛋白：（i）保留在内质网和中间高尔基体区室中，（ii）不能进行晚期高尔基体加工，和（iii）经受加速降解，细胞内转运的阻断，加速周转，C282 Y蛋白不能正常呈递到细胞表面，这为HH中该突变蛋白的功能受损提供了可能的基础。
Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder known in humans, A candidate gene for HH called HFE has recently been cloned that encodes a novel member of the major histocompatibility complex class I family, Most HH patients are homozygous for a Cys-282 --> Tyr (C282Y) mutation in HFE gene, which has been shown to disrupt interaction with beta(2)-microglobulin; a second mutation, His-63 --> Asp (H63D), is enriched in HH patients who are heterozygous for C282Y mutation, The aims of this study were to determine the effects of the C282Y and H63D mutations on the cellular trafficking and degradation of the HFE protein in transfected COS-7 cells, The results indicate that, while the wild-type and H63D HFE proteins associate with beta(2)-microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein, We present biochemical and immunofluorescence data that indicate that the C282Y mutant protein: (i) is retained in the endoplasmic reticulum and middle Golgi compartment, (ii) fails to undergo late Golgi processing, and (iii) is subject to accelerated degradation, The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provide a possible basis for impaired function of this mutant protein in HH.