Non-coding RNAs in Wilson's Disease: Plausible drivers of hepatic symptom heterogeneity

Wilson's disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, which impair cellular copper excretion and lead to toxic copper accumulation in the liver, brain, and other organs. Clinically, WD presents with a broad spectrum of hepatic and neurological manifestations. The pronounced phenotypic variability among patients harboring identical ATP7B mutations, including affected siblings, suggests the influence of additional genetic and/or epigenetic factors such as non-coding RNAs (ncRNAs), in modulating disease presentation. This review explores the potential involvement of ncRNAs in shaping the hepatic phenotype of WD. Although a few transcriptomic and network-based studies in mouse models have underscored the relevance of ncRNAs in WD pathogenesis, there remains a paucity of research investigating their role in the spectrum of hepatic severity observed in human patients. To address this gap, we collated existing evidence on ncRNAs implicated in WD and further sought to predict additional candidate ncRNAs by aligning hepatic severity categories in WD with general liver diseases that exhibit similar clinical features. Through a systematic literature review, we identified dysregulated ncRNAs in these liver diseases that may serve as surrogates for WD severity groups. Furthermore, our in silico analyses highlighted several microRNAs (miRNAs) that, if upregulated, could downregulate ATP7B or its putative modifier genes, raising the possibility that miRNA dysregulation may phenocopy certain pathogenic effects of ATP7B mutations, especially in WD cases exhibiting missing heritability.