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

Gastroenterology. 2001 Mar;120(4):967-74. doi: 10.1053/gast.2001.22543.


Background & aims: Wilson disease is a genetic disorder characterized by the accumulation of copper in the body as a result of a defect of copper excretion from hepatocytes. The intracellular localization of the Wilson disease gene product, ATP7B, was recently identified as the late endosomes. Various mutations have been documented in patients with Wilson disease. The clinical manifestations vary greatly among the patients; however, there is little information on the genotype-phenotype correlation.

Methods: We investigated the distribution of a common ATP7B mutant His1069Gln and a mutant Asp1270Ser by expressing the mutants tagged with green fluorescent protein in Huh7 and HEK293 cells. Intracellular organelles were visualized by fluorescence microscopy.

Results: Although the wild-type ATP7B and Asp1270Ser mutant localized in the late endosomes, His1069Gln mutant did not locate in the late endosomes and was degraded by the proteasomes in the cytoplasm. Furthermore, His1069Gln formed aggresomes composed of the degradates and intermediate filaments at the microtubule-organizing center. These aggresomes were similar to Mallory bodies on electron microscopy.

Conclusions: The different protein properties of ATP7B mutants may explain the variety of clinical spectrums in patients with Wilson disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cation Transport Proteins*
  • Cell Line
  • Copper-Transporting ATPases
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / physiology*
  • Cysteine Endopeptidases / ultrastructure
  • Cytoskeleton / ultrastructure
  • Fluorescent Antibody Technique
  • Humans
  • Leupeptins / pharmacology
  • Microscopy, Confocal
  • Microscopy, Electron
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / physiology*
  • Multienzyme Complexes / ultrastructure
  • Mutation / physiology*
  • Proteasome Endopeptidase Complex
  • Tissue Distribution


  • Carrier Proteins
  • Cation Transport Proteins
  • Leupeptins
  • Multienzyme Complexes
  • acetylleucyl-leucyl-norleucinal
  • lactacystin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • ATP7B protein, human
  • Copper-Transporting ATPases
  • Acetylcysteine