Medici Valentina, Huster Dominik
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA.
Department of Gastroenterology and Oncology, Deaconess Hospital Leipzig, Leipzig, Germany.
Handb Clin Neurol. 2017;142:57-70. doi: 10.1016/B978-0-444-63625-6.00006-9.
Wilson disease (WD) is caused by ATPase copper-transporting beta (ATP7B) mutations and results in copper toxicity in liver and brain. Although the defective gene was identified in 1993, the specific mechanisms underlying copper toxicity and the remarkable phenotypic diversity of the disease are still poorly understood. Animal models harboring defects in the ATP7B homolog have helped to reveal new insights into pathomechanisms of WD. Four rodent models with ATP7B gene defects have been described - the Long-Evans Cinnamon (LEC) rat, inbred mouse models (toxic milk (tx), the Jackson Laboratory toxic milk (tx-j)), and the genetically engineered ATP7B (knockout) mouse - all of which develop liver disease to different extents. Copper accumulation in parts of the brain accompanied by some neurologic involvement was revealed in LEC rats and tx/tx-j mice, but the pathology is less severe than human neurologic WD. Several dogs show hepatic copper toxicity resembling WD; however, brain involvement has not been observed and the underlying genetic defect is different. These models are of great value for examination of copper distribution and metabolism, gene expression, and investigation of liver and brain pathology. The availability of disease models is essential for therapeutic interventions such as drug, gene, and cell therapy. Findings made by animal studies may facilitate the development of specific therapies to ameliorate WD progression.
威尔逊病（WD）由ATP酶铜转运β（ATP7B）突变引起，导致肝脏和大脑中的铜毒性。尽管缺陷基因于1993年被鉴定出来，但铜毒性的具体机制以及该疾病显著的表型多样性仍知之甚少。携带ATP7B同源物缺陷的动物模型有助于揭示WD发病机制的新见解。已描述了四种具有ATP7B基因缺陷的啮齿动物模型——长-伊文斯肉桂色（LEC）大鼠、近交小鼠模型（毒性乳鼠（tx）、杰克逊实验室毒性乳鼠（tx-j））以及基因工程ATP7B（敲除）小鼠——所有这些模型都会在不同程度上发展为肝脏疾病。在LEC大鼠和tx/tx-j小鼠中发现大脑部分区域有铜蓄积，并伴有一些神经受累情况，但病理表现比人类神经型WD轻。几只狗表现出类似WD的肝铜毒性；然而，未观察到脑部受累情况，且潜在的基因缺陷不同。这些模型对于检查铜的分布和代谢、基因表达以及研究肝脏和脑部病理具有重要价值。疾病模型的可用性对于药物、基因和细胞治疗等治疗干预至关重要。动物研究的结果可能有助于开发特定疗法以改善WD的进展。
