Systems biology approach to Wilson's disease

Abstract

Wilson's disease (WD) is a severe disorder of copper misbalance, which manifests with a wide spectrum of liver pathology and/or neurologic and psychiatric symptoms. WD is caused by mutations in a gene encoding a copper-transporting ATPase ATP7B and is accompanied by accumulation of copper in tissues, especially in the liver. Copper-chelation therapy is available for treatment of WD symptoms and is often successful, however, significant challenges remain with respect to timely diagnostics and treatment of the disease. The lack of genotype-phenotype correlation remains unexplained, the causes of fulminant liver failure are not known, and the treatment of neurologic symptoms is only partially successful, underscoring the need for better understanding of WD mechanisms and factors that influence disease manifestations. Recent gene and protein profiling studies in animal models of WD began to uncover cellular processes that are primarily affected by copper accumulation in the liver. The results of such studies, summarized in this review, revealed new molecular players and pathways (cell cycle and cholesterol metabolism, mRNA splicing and nuclear receptor signaling) linked to copper misbalance. A systems biology approach promises to generate a comprehensive view of WD onset and progression, thus helping with a more fine-tune treatment and monitoring of the disorder.

Fig. 1

The top 10 canonical signaling pathways down-regulated in LEC rats (top) and Atp7b^−/− mice (bottom). Differentially expressed genes (greater than 1.5 fold) were derived from comparing 6-week old Atp7b^−/− to wild-type littermates; or 26 week old LEC rats—to 4 week old LEC rats. Ingenuity Pathway Analysis (IPA) defined 218 genes from Atp7b^−/− and 1208 from LEC rats eligible for pathway analysis. These genes were queried against the IPA pathway library to identify over-represented signaling pathways that were significantly down-regulated. The significance [–log (P-value)] of a given pathway is measured by the likelihood that the pathway is associated with the dataset by random chance using the Fischer’s exact test. Striped bars Pathways common to Atp7b^−/− mice and LEC rats. Black bars Pathways unique to Atp7b^−/− mice or LEC rats. *Pathways involved in lipid or steroid metabolism

Fig. 2

The most populated network of genes up-regulated in 6 week old Atp7b^−/− mice as defined by Ingenuity Network analysis. Shaded symbols represent transcripts for which the change in abundance was experimentally demonstrated