MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy
MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy
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DOI：
10.1093/brain/awt012
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发表时间：
2013-03-01
期刊：
影响因子：
14.5
通讯作者：
Dionisi-Vici, Carlo
中科院分区：
文献类型：
--
作者：
Martinelli, Diego;Travaglini, Lorena;Dionisi-Vici, Carlo
MEDNIK综合征--智力低下、肠病、耳聋、神经病、鱼鳞病、角化病的首字母缩写--是由AP 1 S1基因突变引起的，编码Sigma 1A，衔接蛋白1复合物的小亚基，在网格蛋白外壳组装中起关键作用，并介导trans-Golgi网络、内体和质膜之间的运输。MEDNIK综合征首先在几个有共同祖先的法裔加拿大家庭中报道，表现为复杂的神经皮肤表型，但其发病机制尚不完全清楚。一名携带新的AP 1 S1纯合突变的Sephardic-犹太人患者表现出严重的铜代谢紊乱，伴有低铜血症、低铜蓝蛋白血症和肝铜蓄积，沿着肝内胆汁淤积。醋酸锌治疗显著改善临床状况，以及肝铜和胆汁酸超载。我们在最初的法国-加拿大患者系列中回顾性评价了铜相关代谢物和肝功能。在患者成纤维细胞中研究细胞内铜代谢和铜泵ATP 7A的亚细胞定位和功能。所有患者均出现铜代谢紊乱和肝病。在突变体成纤维细胞的研究表明，异常的铜掺入和保留，铜依赖性酶细胞色素c氧化酶和铜/锌超氧化物歧化酶的表达减少，和异常的细胞内运输的门克斯蛋白ATP 7A，恢复正常后实验表达野生型AP 1 S1基因。我们解决了MEDNIK综合征的发病机制，证明AP 1 S1通过铜泵蛋白介导调节细胞内铜机制。这种多系统疾病的特点是一个独特的图片，结合临床和生化标志的门克斯和威尔逊的疾病，其中肝脏铜超载是可治疗的醋酸锌治疗，现在可以列为铜代谢缺陷的人。我们的研究结果也可能有助于理解铜泵的细胞内运输机制。
MEDNIK syndrome-acronym for mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia-is caused by AP1S1 gene mutations, encoding Sigma 1A, the small subunit of the adaptor protein 1 complex, which plays a crucial role in clathrin coat assembly and mediates trafficking between trans-Golgi network, endosomes and the plasma membrane. MEDNIK syndrome was first reported in a few French-Canadian families sharing common ancestors, presenting a complex neurocutaneous phenotype, but its pathogenesis is not completely understood. A Sephardic-Jewish patient, carrying a new AP1S1 homozygous mutation, showed severe perturbations of copper metabolism with hypocupremia, hypoceruloplasminemia and liver copper accumulation, along with intrahepatic cholestasis. Zinc acetate treatment strikingly improved clinical conditions, as well as liver copper and bile-acid overload. We evaluated copper-related metabolites and liver function retrospectively in the original French-Canadian patient series. Intracellular copper metabolism and subcellular localization and function of copper pump ATP7A were investigated in patient fibroblasts. Copper metabolism perturbation and hepatopathy were confirmed in all patients. Studies in mutant fibroblasts showed abnormal copper incorporation and retention, reduced expression of copper-dependent enzymes cytochrome-c-oxidase and Cu/Zn superoxide dismutase, and aberrant intracellular trafficking of Menkes protein ATP7A, which normalized after rescue experiments expressing wild-type AP1S1 gene. We solved the pathogenetic mechanism of MEDNIK syndrome, demonstrating that AP1S1 regulates intracellular copper machinery mediated by copper-pump proteins. This multisystem disease is characterized by a unique picture, combining clinical and biochemical signs of both Menkes and Wilson's diseases, in which liver copper overload is treatable by zinc acetate therapy, and can now be listed as a copper metabolism defect in humans. Our results may also contribute to understand the mechanism(s) of intracellular trafficking of copper pumps.