Theophilos M B, Cox D W, Mercer J F
Scobie and Clare Mackinnon Trace Element Laboratory, Murdoch Institute, Royal Children's Hospital, Parkville, Australia.
Hum Mol Genet. 1996 Oct;5(10):1619-24. doi: 10.1093/hmg/5.10.1619.
Wilson disease (WD) is an autosomal recessive defect of copper transport characterized by massive accumulation of copper in the liver, which can lead to liver failure. Mutations in a copper transporting ATPase (WND or ATP7B) have been shown to cause the disease. The toxic milk mouse mutant (tx) accumulates copper in the liver in a manner similar to that observed in patients with WD. However, some physiological differences between tx mice and human WD patients have cast doubts on whether this mutant mouse is a valid model for WD. In this paper we report the isolation of cDNA clones encoding the murine homologue of WND. The predicted amino acid sequence is 1462 amino acids and contains the same functional domains identified in human and rat WND. As in the rat, the fourth metal binding domain is apparently non-functional. Similar levels of a 7.5 kb WND mRNA were detected in liver and kidney from normal and tx mice, indicating that transcription of this gene was unaffected in the mutant mice. The coding sequence of WND cDNA from the tx mouse liver identified a single nucleotide difference between the normal DL mouse and the tx which is predicted to change methionine 1356 in the eighth transmembrane domain to valine. This methionine is conserved in all copper ATPases including those from bacteria and yeast. The conclusion that this is the causative mutation is supported by the recent mapping of tx and WND to the same region of mouse chromosome 8. Thus the tx mouse is presented as a valid model for studies of the role of WND in copper transport and for investigation of different treatment strategies for WD.
威尔逊病（WD）是一种常染色体隐性铜转运缺陷病，其特征是肝脏中大量铜蓄积，可导致肝衰竭。已证实铜转运ATP酶（WND或ATP7B）的突变会引发该病。毒性乳鼠突变体（tx）肝脏中铜的蓄积方式与WD患者相似。然而，tx小鼠与人类WD患者之间的一些生理差异使人怀疑该突变小鼠是否是WD的有效模型。在本文中，我们报告了编码WND小鼠同源物的cDNA克隆的分离。预测的氨基酸序列有1462个氨基酸，包含在人类和大鼠WND中鉴定出的相同功能域。与大鼠一样，第四个金属结合域显然无功能。在正常小鼠和tx小鼠的肝脏和肾脏中检测到相似水平的7.5 kb WND mRNA，表明该基因的转录在突变小鼠中未受影响。来自tx小鼠肝脏的WND cDNA编码序列在正常DL小鼠和tx小鼠之间鉴定出一个单核苷酸差异，预计该差异会将第八个跨膜结构域中的甲硫氨酸1356变为缬氨酸。该甲硫氨酸在所有铜ATP酶中都保守，包括来自细菌和酵母的铜ATP酶。tx和WND最近被定位到小鼠8号染色体的同一区域，这支持了这是致病突变的结论。因此，tx小鼠被认为是研究WND在铜转运中的作用以及研究WD不同治疗策略的有效模型。
