Ambrosini L, Mercer J F
The Murdoch Institute, Royal Children's Hospital, Flemington Road, Parkville 3052, Australia.
Hum Mol Genet. 1999 Aug;8(8):1547-55. doi: 10.1093/hmg/8.8.1547.
Menkes disease is an X-linked disorder of copper metabolism. An overall copper deficiency reduces the activity of copper-dependent enzymes accounting for the clinical presentation of affected individuals. The Menkes gene product (MNK) is a P-type ATPase and is considered to be the main copper efflux protein in most cells. The protein is located primarily at the trans -Golgi network (TGN), but relocalizes to the plasma membrane in elevated copper conditions to expel the excess copper from the cell. Here we report the first missense mutation which causes mild Menkes disease, a mutation in a successfully copper-treated classical Menkes patient and the effect of each mutation on the localization of MNK within the cell. Using western blot analysis, MNK was detectable in cells from both patients, but appeared to be mislocalized in the treated case. In the mild Menkes patient, the protein appeared to be located in the TGN but failed to redistribute towards the cell periphery in response to copper. This is the first description of a mutation in a Menkes patient which affects the trafficking of MNK, and the loss of this process is consistent with the clinical phenotype.
门克斯病是一种X连锁的铜代谢紊乱疾病。整体铜缺乏会降低铜依赖性酶的活性，这导致了受影响个体的临床表现。门克斯基因产物（MNK）是一种P型ATP酶，被认为是大多数细胞中的主要铜外排蛋白。该蛋白主要位于反式高尔基体网络（TGN），但在铜含量升高的情况下会重新定位到质膜，以将多余的铜排出细胞。在这里，我们报告了首例导致轻度门克斯病的错义突变、一名经成功铜治疗的典型门克斯病患者中的突变以及每个突变对MNK在细胞内定位的影响。使用蛋白质印迹分析，在两名患者的细胞中均检测到MNK，但在经治疗的病例中似乎定位错误。在轻度门克斯病患者中，该蛋白似乎位于TGN，但在铜的作用下未能重新分布到细胞周边。这是首次描述门克斯病患者中影响MNK运输的突变，而这一过程的缺失与临床表型一致。
