Menkes综合征——细胞内铜转运缺陷的研究

DEFECTIVE INTRACELLULAR COPPER TRANSLOCATION IN MENKES KINKY HAIR SYNDROME

Menkes综合征是一种致死性X-连锁隐性遗传病,以铜代谢障碍和进行性中枢神经系统损害为特征,其病因和发病机理仍不清楚。作者通过对培养的正常型和Menkes型成纤维细胞内铜分布特点的研究,并与锌和镉细胞内的分布相比较,发现:(1)突变型细胞内铜含量显著增高,分析其在细胞内胞液(Cytosol)组份和颗粒(Particulate)组份中的分布,发现铜被"封阻"的现象;(2)在实验条件下使正常细胞与突变细胞内铜含量互相重叠,在正常细胞中,铜从胞液组份迅速地移到颗粒组份中,而在突变细胞中,铜仍被"封阻"在胞液组份中;(3)在正常细胞中,铜在细胞组份间的位移需依赖于蛋白质的合成;(4)Menkes突变专一性地影响铜在细胞内的代谢,对其它金属的代谢无影响,据此提出Menkes综合征的原发病因很可能在于细胞内铜转运移位的缺陷的假设。

Menkes kinky hair syndrome is a lethal X-linked neurodegenerative disorder causing tissure specific increases in copper (Cu)concentration. The basic defect of this disease is unknown. This study, experimentally, compared the distribution of Cu and other trace metals (Zn, Cd) between the cellular particulate and cytosol fractions in normal and Menkes cultural fibroblasts and revealed that: (1) the Cu content in Menkes cells was remarkably increased and Cu sequestration between the particulate and cytosol fractions occurred; (2) even an overlap- ping range of cytosolic Cu concentration in both normal and Menkes cells, the particulate Cu content in Menkes remained significantly lower than in normals; (3) Cu distribution in cell compartments was dependent on a process of protein synthesis; (4) Menkes mutation specifically disturbanced Cu intracellular distribution but not interfered in ether trace metals. All these results indicated that a major consequence of Menkes mutation is a specific failure of Cu transloation across a cell compartment.