ATP7A-related copper transport diseases-emerging concepts and future trends.
ATP7A-related copper transport diseases-emerging concepts and future trends.
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DOI：
10.1038/nrneurol.2010.180
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发表时间：
2011-01
影响因子：
38.1
通讯作者：
Kaler, Stephen G.
中科院分区：
文献类型：
--
作者：
Kaler, Stephen G.
本文综述了近年来对铜转运ATPase 1 （ATP7A）的研究进展，并探讨了与该蛋白功能障碍相关的神经表型。ATP7A参与轴突生长、突触完整性和神经元激活，强调了铜代谢对神经功能的根本重要性。ATP7A缺陷导致Menkes病，这是一种婴儿发病的致命疾病。新生儿诊断和早期铜注射治疗可提高该病患者的生存率，如果突变ATP7A分子保留少量残留活性，则可使临床结果正常化。基因替代拯救了Menkes病的小鼠模型，为完全丧失功能的ATP7A突变患者提供了一种潜在的治疗方法。值得注意的是，一种新发现的ATP7A疾病——孤立的远端运动神经病——没有Menkes病或其较轻的等位变异枕角综合征（OHS）的特征性临床或生化异常，而是类似于2型charco - mary - tooth病。这些研究结果表明，ATP7A在运动神经元维持中具有至关重要但以前未被认识到的作用，并且ATP7A相关的远端运动神经病变的机制与Menkes病和OHS病理生理不同。总的来说，这些见解完善了我们对ATP7A相关铜转运疾病的神经学知识，并为进一步了解ATP7A功能铺平了道路。
This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder—isolated distal motor neuropathy—has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot–Marie–Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.
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