La Fontaine S L, Firth S D, Camakaris J, Englezou A, Theophilos M B, Petris M J, Howie M, Lockhart P J, Greenough M, Brooks H, Reddel R R, Mercer J F
The Murdoch Institute Royal Children's Hospital, Parkville 3052, Australia.
J Biol Chem. 1998 Nov 20;273(47):31375-80. doi: 10.1074/jbc.273.47.31375.
Menkes' disease is a fatal, X-linked, copper deficiency disorder that results from defective copper efflux from intestinal cells and inadequate copper delivery to other tissues, leading to deficiencies of critical copper-dependent enzymes. Wilson's disease is an autosomally inherited, copper toxicosis disorder resulting from defective biliary excretion of copper, which leads to copper accumulation in the liver. The ATP7A and ATP7B genes that are defective in patients with Menkes' and Wilson's diseases, respectively, encode transmembrane, P-type ATPase proteins (ATP7A or MNK and ATP7B or WND, respectively) that function to translocate copper across cellular membranes. In this study, the cDNAs derived from a normal human ATP7A gene and the murine ATP7B homologue, Atp7b, were separately transfected into an immortalized fibroblast cell line obtained from a Menkes' disease patient. Both MNK and WND expressed from plasmid constructs were able to correct the copper accumulation and copper retention phenotype of these cells. However, the two proteins responded differently to elevated extracellular copper levels. Although MNK showed copper-induced trafficking from the trans-Golgi network to the plasma membrane, in the same cell line the intracellular location of WND did not appear to be affected by elevated copper.
门克斯病是一种致命的、X连锁的铜缺乏症，由肠道细胞铜外流缺陷和铜向其他组织输送不足导致，从而引发关键铜依赖性酶的缺乏。威尔逊病是一种常染色体隐性遗传的铜中毒症，由铜的胆汁排泄缺陷引起，导致铜在肝脏中蓄积。分别在门克斯病和威尔逊病患者中存在缺陷的ATP7A和ATP7B基因，编码跨膜P型ATP酶蛋白（分别为ATP7A或MNK以及ATP7B或WND），其功能是使铜跨细胞膜转运。在本研究中，将源自正常人ATP7A基因和小鼠ATP7B同源物Atp7b的cDNA分别转染到从一名门克斯病患者获得的永生化成纤维细胞系中。从质粒构建体表达的MNK和WND都能够纠正这些细胞的铜蓄积和铜潴留表型。然而，这两种蛋白对细胞外铜水平升高的反应不同。尽管MNK显示出铜诱导的从反式高尔基体网络向质膜的转运，但在同一细胞系中，WND的细胞内定位似乎不受铜升高的影响。
