ACERULOPLASMINEMIA - MOLECULAR CHARACTERIZATION OF THIS DISORDER OF IRON-METABOLISM
ACERULOPLASMINEMIA - MOLECULAR CHARACTERIZATION OF THIS DISORDER OF IRON-METABOLISM
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DOI：
10.1073/pnas.92.7.2539
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发表时间：
1995-03-28
影响因子：
11.1
通讯作者：
GITLIN, JD
中科院分区：
文献类型：
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作者：
HARRIS, ZL;TAKAHASHI, Y;GITLIN, JD
血浆铜蓝蛋白是一种丰富的血清糖蛋白，其含有脊椎动物血浆中发现的95%的铜。我们在这里报告的铜蓝蛋白基因的遗传缺陷的鉴定，以前注意到有一个总的循环血清铜蓝蛋白与迟发性视网膜和基底节变性的患者。在这个病人的T-2（横向弛豫时间）加权磁共振成像的大脑显示基底神经节密度与铁沉积一致，肝活检证实存在过量的铁。虽然Southern印迹分析的患者的DNA是正常的，PCR扩增的18个外显子组成的人铜蓝蛋白基因显示了显着的大小差异外显子7。该外显子的DNA序列分析显示在氨基酸410处插入5-bp，导致移码突变和截短的开放阅读框。该突变的有效性通过对患者女儿的DNA分析得到证实，该分析揭示了该相同5-bp插入的杂合性。该突变的存在与临床和病理结果相结合，证明了血浆铜蓝蛋白在人类生物学中的重要作用，并将血浆铜蓝蛋白血症确定为常染色体隐性铁代谢疾病。这些研究结果支持以前的研究，确定铜蓝蛋白作为一种铁氧化酶，是非常一致的同源铜氧化酶在酵母铁代谢中的重要作用与最近的研究。临床和实验室结果表明，额外的患者与运动障碍和非经典威尔逊病应检查铜蓝蛋白基因突变。
Ceruloplasmin is an abundant cut-serum glycoprotein that contains 95% of the copper found in the plasma of vertebrate species. We report here on the identification of a genetic defect in the ceruloplasmin gene in a patient previously noted to have a total absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration. In this patient T-2 (transverse relaxation time)-weighted magnetic resonance imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410, resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patient's daughter, which revealed heterozygosity for this same 5-bp insertion, The presence of this mutation in conjunction with the clinical and pathologic findings demonstrates an essential role for ceruloplasmin in human biology and identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism. These findings support previous studies that identified ceruloplasmin as a ferroxidase and are remarkably consistent with recent studies on the essential role of a homologous copper oxidase in iron metabolism in yeast. The clinical and laboratory findings suggest that additional patients with movement disorders and nonclassical Wilson disease should be examined for ceruloplasmin gene mutations.