Classification of mutations in ATP7B in Wilson’s disease patients

Abstract

Background: The impact of individual ATP7B mutations on the diversity of the clinical spectrum of Wilson’s disease (WD) is not understood yet. Material and methods: The functional activity of ATP7B has been assessed and compared to the reports of the homozygous WD patients. Ten rare and two frequent mutations H1069Q and R969Q have been selected after the analysis of the literature in question. Chinese hamster ovary cell lines lacking ATP7B expression and carrying the selected mutations have been generated. The cells have been characterized by transgenic ATP7B activity by the determination of copper accumulation and copper toxicity. Results: The highly concordant results have been observed in the diverse functional activities of ATP7B within the groups of mutations that were established with regard to the disease onset reported in the patients. Whereas a low (< 29 ± 3% of wild type of ATP7B) or no ATP7B activity has been found in the group of the mutations (n = 5) observed in the patients with early (or sudden) onset of the disease, its high activity (77.6 ± 7% to 118.6 ± 7%) has been observed in the group of the patients with the late onset of the disease (n = 3). Notably, the mutations H1069Q and R969Q of the third group (n = 4) showing predominately the intermediate time of the disease onset have had a moderate level of ATP7B activity. Conclusions: The data suggest that in the functional assessment of ATP7B mutations in homozygous patients we can single out the groups that have distinct grades of biologic activity which improves our understanding of the high degree of phenotypic variation observed in WD patients as well as the data on the onset of the disease.