Genetics and epigenetic factors of Wilson disease

Valentina Medici, Janine M. LaSalle


Wilson disease (WD) is a complex condition due to copper accumulation mainly in the liver and brain. The genetic base of WD is represented by pathogenic mutations of the copper-transporting gene ATP7B with consequent lack of copper excretion through the biliary tract. ATP7B is the only gene so far identified and known to be responsible for the development of the disease. Our understanding of the disease has been evolving as functional studies have associated specific disease-causing mutations with specific copper-transporter impairments. The most frequent variant in patients of European descent is the H1069Q missense mutation and it has been associated with protein misfolding, aberrant phosphorylation of the P-domain, and altered ATP binding orientation and affinity. Conversely, there is much less understanding of the relation between the genotype and the clinical manifestations of WD. WD is characterized by a highly varied and unpredictable presentation with different combined hepatic, neurological, and psychiatric symptoms. Several studies have attempted to correlate genotype and phenotype but the most recent evidences on larger populations failed to identify a relation between genotype and clinical presentations. Given that so far also modifier genes have not shown convincing association with WD, there is growing interest to identify epigenetic mechanisms of gene expression regulation as underlying the onset and progression of WD phenotype. Evidence from animal models indicated changes in methionine metabolism regulation with possible effects on DNA methylation. Mouse models of WD have indicated transcript level changes of genes related to DNA methylation in fetal and adult livers. And finally, evidence is accumulating regarding DNA methylation changes in patients with WD. It is unexplored how ATP7B genetic mutations combine with epigenetic changes to affect the phenotype. In conclusion, WD is a genetic disease with a complex regulation of its phenotype that includes molecular genetics and epigenetic mechanisms.