Abstract
Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by defects in the ATPase gene (ATP7B). The various clinical features result from the massive accumulation of copper in the liver, cornea and basal ganglia. Although WD can be effectively treated with proper medicine, this disease is difficult to clearly diagnose due to its indefinite symptoms. In the current study, we achieved a positive correlation between clinical symptoms and the enzymatic activity of ceruloplasmin in WD patients. Furthermore, proteome profiles of plasma as well as network analysis demonstrated that fibrinogen is a critical indicator which is significantly unregulated in WD subjects in comparison to healthy donors and closely linked to pathogenesis of WD. Here, we applied 2DE-immunoblots and immunohistochemistry to verify the protein level and localization in situ. The enhanced expression of fibrinogen in the plasma of WD subjects with respect to that of healthy controls and patients with distinct disorders was also confirmed by utilizing clinical samples. As expected, application of high dose of copper induced expression of fibrinogen, while knockdown of ceruloplasmin also resulted in upregulation of fibrinogen as well as elimination of superoxide dismutase (SOD), leading to increased oxidative stress in cells. In summary, the liver injury or oxidative stress induced by the progression of WD may account for the obvious increase of fibrinogen, which in turn triggers inflammatory responses and interferes coagulation cascades; this finding sheds light on the early detection and diagnosis of WD.
Highlights
Wilson’s disease (WD) is hereditable and affects approximately one in 30,000 individuals worldwide, with exceptions found in specific subgroups with consanguinity [1]
After quantitative analysis divided by internal control, the enzymatic activity attained to almost 100% in the plasma of sample S; it showed significant decrease by 95% in sample WD and 90% in sample B
According to the results from the proteome alternation profiles, we suggest that fibrinogen may be an important index in plasma of WD patients due to hepatic injury, as it was dominant in the Taiwan WD patients
Summary
Wilson’s disease (WD) is hereditable and affects approximately one in 30,000 individuals worldwide, with exceptions found in specific subgroups with consanguinity [1]. Over hundred mutations of ATP7B, including point mutations, deletions and frame-shift, have been reported in patients with WD. Most patients have two different mutations of the gene on each allele encoding the WD gene, called compound heterozygotes [2,3]. This protein product is similar to other ATP-dependent transporters for heavy metals, which is mainly expressed in the liver and mediates copper homeostasis in liver cells. Affected patients usually present liver diseases such as inflammation, cirrhosis or fulminant liver failure. Patients cannot always fully recover from toxic levels of copper resulting in permanent liver or neurological deficits because of irreversible tissue damage [7,8]
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