Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes.
Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes.
复制标题
乙基丙二酸脑病、线粒体病和铜缺乏表型患者铜转运蛋白基因的突变分析。
DOI：
10.1023/a:1024027630589
复制
发表时间：
2003
影响因子：
4.2
通讯作者：
Packman,S
中科院分区：
文献类型：
--
作者：
Fu,X;Rinaldo,P;Hahn,SH;Kodama,H;Packman,S
微量金属铜是许多生物过程的重要辅助因子，包括线粒体氧化磷酸化，自由基清除，神经递质合成和成熟以及铁代谢。因此，铜在细胞表面的转运和铜向细胞内蛋白质的递送是正常细胞内稳态中的关键事件。据报道，有四种基因影响细胞摄取和铜向特定细胞区室和蛋白质的递送。这些包括hCTR 1，其调节细胞铜摄取; HAH 1，其介导铜向门克斯和威尔逊病转运蛋白的转移; CCS，其与铜向超氧化物歧化酶的转移有关;和hCOX 17，其指导铜向线粒体细胞色素氧化酶的运输。目前，没有遗传性疾病与这四个铜转运蛋白基因的缺陷有关。在这项研究中，我们测试的可能性，有缺陷的铜吸收或细胞内易位代表的基本缺陷，在三个类别的候选表型22例：乙基丙二酸脑病，不明病因的神经系统疾病和神经发育异常的临床和化学证据铜缺乏症。通过直接测序整个编码区进行铜摄取蛋白、hCTR 1和三种铜分子伴侣的突变分析。在22例患者中，未发现四种铜转运蛋白基因的致病突变。在7例患者中检测到CCS基因杂合多态性（847 G>A）。对于不同的疾病实体乙基丙二酸脑病，我们还显示了四个基因中每一个的正常mRNA水平。尽管结果是阴性的，但我们鼓励继续研究具有候选表型的其他患者。此外，我们的结果与其他未知的铜相关转运蛋白可能参与疾病的概念一致。
Summary:The trace metal copper is an essential cofactor for a number of biological processes, including mitochondrial oxidative phosphorylation, free‐radical eradication, neurotransmitter synthesis and maturation, and iron metabolism. Consequently, copper transport at the cell surface and the delivery of copper to intracellular proteins are critical events in normal cellular homeostasis. Four genes have been reported to influence the cellular uptake and the delivery of copper to specific cell compartments and proteins. These include hCTR1, which regulates cellular copper uptake; HAH1, which mediates the transfer of copper to the Menkes and Wilson disease transporters; CCS, which is related to the transfer of copper to superoxide dismutase; and hCOX17, which directs trafficking of copper to mitochondrial cytochrome‐coxidase. At present, no genetic disorders have been associated with defects in these four copper transporter genes. In this study, we test the possibility that defective copper uptake or intracellular translocation represents the basic defect in three categories of candidate phenotypes among 22 patients: ethylmalonic encephalopathy; mitochondriopathies of unknown aetiology; and neurodevelopmental abnormalities with clinical and chemical evidence of copper deficiency. Mutation analyses of the copper uptake protein, hCTR1, and the three copper chaperones were performed by direct sequencing of the whole coding regions. No causative mutations were identified for the four copper transporter genes in 22 patients. A heterozygous polymorphism (847G>A) for CCS was detected in 7 patients. For the distinct disease entity ethylmalonic encephalopathy, we additionally show normal mRNA levels for each of the four genes. The negative results notwithstanding, we encourage ongoing study of additional patients with candidate phenotypes. Further, our results are consistent with the notion that other unknown copper‐related transporters could be involved in diseases.