Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines

Gursimran Chandhok, Judit Horvath, Annu Aggarwal, Mohit Bhatt, Andree Zibert, Hartmut H.J. Schmidt

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21 Citations (Scopus)


AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7B mutations in cell culture. METHODS: The most common Wilson disease (WD) mutations p.H1069Q, p.R778L and p.C271∗, found in the ATP7B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7B was used to stably express WD mutants. mRNA and protein expression of mutant ATP7B , survival of cells, apoptosis, and protein trafficking were determined. RESULTS: Low temperature increased ATP7B protein expression in several mutants. Intracellular ATP7B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069Q and to a lesser extent p.C271∗ improved by D-penicillamine (DPA) treatment, while mutant p.R778L showed a pronounced response to zinc (Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability. CONCLUSION: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.

Original languageEnglish
Pages (from-to)4109-4119
Number of pages11
JournalWorld Journal of Gastroenterology
Issue number16
Publication statusPublished - 28 Apr 2016
Externally publishedYes


  • Atp7b
  • D-penicillamine
  • Mutations
  • Therapy
  • Wilson disease
  • Zinc

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