Davis W, Chowrimootoo G F, Seymour C A
Department of Clinical Biochemistry and Metabolism, St George's Hospital Medical School, London, UK.
Eur J Clin Invest. 1996 Oct;26(10):893-901. doi: 10.1111/j.1365-2362.1996.tb02135.x.
Previous studies have failed to explain the link between copper accumulation and abnormal caeruloplasmin expression in Wilson's disease. Furthermore, despite the isolation of a candidate gene for Wilson's disease, which predicts a defective copper transport protein, the localization of this putative protein and its relationship to the pathway involved in copper excretion and to caeruloplasmin remain unknown. We now present evidence that caeruloplasmin, the major plasma copper-carrying protein, is present in the liver in Wilson's disease, and thus that reduced circulating levels of the protein result from a post-translational defect in the secretory pathway. We have also identified a novel form of caeruloplasmin, molecular weight 125 kD, which we propose may act as the carrier for excretory copper into bile, since it is normally present in both liver and bile, although largely absent from serum, and undetectable in bile from Wilson's disease patients. The presence of this form of caeruloplasmin in Wilson's disease liver suggests that a related post-translational defect may also be responsible for its absence from bile in Wilson's disease. This study thus provides the first plausible explanation of a link between the defective copper excretion and the reduced plasma caeruloplasmin, which characterize Wilson's disease.
以往的研究未能解释威尔逊病中铜蓄积与血浆铜蓝蛋白异常表达之间的联系。此外，尽管已分离出威尔逊病的一个候选基因，该基因预测存在一种有缺陷的铜转运蛋白，但这种假定蛋白质的定位及其与铜排泄途径和血浆铜蓝蛋白的关系仍不清楚。我们现在提供证据表明，在威尔逊病中，主要的血浆铜转运蛋白血浆铜蓝蛋白存在于肝脏中，因此该蛋白循环水平降低是由于分泌途径中的翻译后缺陷所致。我们还鉴定出一种分子量为125 kD的新型血浆铜蓝蛋白，我们认为它可能作为排泄性铜进入胆汁的载体，因为它通常同时存在于肝脏和胆汁中，尽管在血清中基本不存在，且在威尔逊病患者的胆汁中检测不到。这种形式的血浆铜蓝蛋白在威尔逊病肝脏中的存在表明，相关的翻译后缺陷也可能是其在威尔逊病胆汁中缺失的原因。因此，本研究首次对威尔逊病所特有的铜排泄缺陷与血浆铜蓝蛋白降低之间的联系给出了合理的解释。
