A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates

Background & Aims: Wilson disease is a genetic disorder characterized by th e accumulation of copper in the body as a result of a defect of copper excr etion from hepatocytes, The intracellular localization of the Wilson diseas e gene product, ATP7B, was recently identified as the late endosomes, Vario us mutations have been documented in patients with Wilson disease. The clin ical manifestations vary greatly among the patients; however, there is litt le information on the genotype-phenotype correlation, Methods: We investiga ted the distribution of a common ATP7B mutant His1069Gln and a mutant Asp12 70Ser by expressing the mutants tagged with green fluorescent protein in Hu h7 and HEK293 cells, Intracellular organelles were visualized by fluorescen ce microscopy, Results: Although the wild-type ATP7B and Asp1270Ser mutant localized in the late endosomes, His1069Gln mutant did not locate in the la te endosomes and was degraded by the proteasomes in the cytoplasm, Furtherm ore, His1069Gln formed aggresomes composed of the degradates and intermedia te filaments at the microtubule-organizing center. These aggresomes were si milar to Mallory bodies on electron microscopy. Conclusions: The different protein properties of ATP7B mutants may explain the variety of clinical spe ctrums in patients with Wilson disease.