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.

Copper: toxicological relevance and mechanisms

“…These findings suggest that altered lipid metabolism may be involved in Cu toxicity. Also, using animal models of Wilson’s disease to study gene and protein profiling, Burkhead et al (2011) have revealed the link between molecular players and pathways, including cell cycle and cholesterol metabolism, mRNA splicing and nuclear receptor signaling, and Cu imbalance, and uncovered cellular processes that are primarily affected by Cu accumulation in the liver.…”

Methanobactin reverses acute liver failure in a rat model of Wilson disease

“…Complete functional loss of ATP7B results in severe WD phenotypes in humans (31,32). The Atp7b -/-rat carries an Atp7b mutation that abolishes its hepatic copper transport activity (16,17). These animals rapidly progress from a copper-burdened liver to hepatic failure and death (18).…”

“…We recently described copper-driven fulminant hepatitis in LPP Atp7b -/-rats that carry a homozygous 13-kb deletion in the Atp7b gene (hereafter referred to as Atp7b -/-rats) (16)(17)(18). Because of this recessive genetic defect, heterozygous Atp7b +/-rats have a normal phenotype.…”

Secondary causes of nonalcoholic fatty liver disease

“…Wilson disease usually presents in the teenage years or young adulthood with symptoms ranging from neurological dysfunction, chronic liver disease, fulminant hepatic failure, isolated acute hemolysis, to psychiatric illness [McCullough et al 1983;Steindl et al 1997]. Wilson disease is caused by mutations in the gene that encodes the copper-transporting ATPase ATP7B [Burkhead et al 2010]. This mutation prevents copper transport into the Golgi complex and binding of copper to apoceruloplasmin.…”