Recent advances in research on high-frequency mutations in the ATP7B gene associated with Wilson disease in the Chinese population: from genetic evolution to precision medicine
TL;DR
A narrative review of the genetic evolution, molecular pathogenic mechanisms, phenotypic heterogeneity, and precision diagnosis and treatment strategies for high-frequency ATP7B mutations in the Chinese WD population is provided.
Abstract
Wilson disease (WD) is a hereditary disorder of copper metabolism caused by mutations in the ATP7B gene; the Chinese population exhibits a unique, high-frequency mutation profile centered on the R778L and P992L mutations. This article provides a narrative review of the genetic evolution, molecular pathogenic mechanisms, phenotypic heterogeneity, and precision diagnosis and treatment strategies for high-frequency ATP7B mutations in the Chinese WD population. The high-frequency enrichment of R778L and P992L is speculated to arise from the combined effects of CpG mutation hotspots and the founder effect supported by East Asian haplotype data, with distinct geographical distributions and relatively conserved haplotypes observed in existing cohorts. Functional studies indicate that the R778L variant disrupts the transmembrane domain and induces severe protein misfolding associated with an early-onset hepatic phenotype, whereas the P992L mutation partially retains catalytic function and tends to present neurological manifestations in many clinical cohorts, though individual phenotypic variation remains substantial. Preclinical molecular chaperone and gene editing strategies offer potential mechanistic targets for mutation-specific intervention, yet their clinical translation remains at an immature stage with insufficient human trial data. In the future, it will be necessary to establish multicenter cohorts, advance mutation-targeted therapies, and develop a precision diagnosis and treatment system covering the entire disease lifecycle.