Diverse functional properties of wilson disease ATP7B variants

Dominik Huster, Angelika Khne, Ashima Bhattacharjee, Lily Raines, Vanessa Jantsch, Johannes Noe, Wiebke Schirrmeister, Ines Sommerer, Osama Sabri, Frieder Berr, Joachim Mssner, Bruno Stieger, Karel Caca, Svetlana Lutsenko

Research output: Contribution to journalArticle

Abstract

Background & Aims: Wilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. Methods: We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells. Protein function was analyzed by measuring catalytic activity and copper ( 64Cu) transport into vesicles. We studied intracellular localization of variants of ATP7B that had measurable transport activities and were tagged with green fluorescent protein in mammalian cells using confocal laser scanning microscopy. Results: Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor-intermediate formation or had partial losses of activity. In mammalian cells, transport-competent variants differed in stability and subcellular localization. Conclusions: Variants in ATP7B associated with Wilson disease disrupt the protein's transport activity, result in its mislocalization, and reduce its stability. Single assays are insufficient to accurately predict the effects of ATP7B variants the function of its product and development of Wilson disease. These findings will contribute to our understanding of genotypephenotype correlation and mechanisms of disease pathogenesis.

Original languageEnglish (US)
JournalGastroenterology
Volume142
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Hepatolenticular Degeneration
Copper
Phenotype
Sf9 Cells
Transport Vesicles
Baculoviridae
Protein Transport
Amino Acid Substitution
Green Fluorescent Proteins
Confocal Microscopy
Adenosine Triphosphatases
Mutation
Genes
Proteins
Therapeutics

Keywords

  • Genetic Analysis
  • Golgi
  • Liver Disease
  • P-Type ATPase

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Huster, D., Khne, A., Bhattacharjee, A., Raines, L., Jantsch, V., Noe, J., ... Lutsenko, S. (2012). Diverse functional properties of wilson disease ATP7B variants. Gastroenterology, 142(4). https://doi.org/10.1053/j.gastro.2011.12.048

Diverse functional properties of wilson disease ATP7B variants. / Huster, Dominik; Khne, Angelika; Bhattacharjee, Ashima; Raines, Lily; Jantsch, Vanessa; Noe, Johannes; Schirrmeister, Wiebke; Sommerer, Ines; Sabri, Osama; Berr, Frieder; Mssner, Joachim; Stieger, Bruno; Caca, Karel; Lutsenko, Svetlana.

In: Gastroenterology, Vol. 142, No. 4, 04.2012.

Research output: Contribution to journalArticle

Huster, D, Khne, A, Bhattacharjee, A, Raines, L, Jantsch, V, Noe, J, Schirrmeister, W, Sommerer, I, Sabri, O, Berr, F, Mssner, J, Stieger, B, Caca, K & Lutsenko, S 2012, 'Diverse functional properties of wilson disease ATP7B variants', Gastroenterology, vol. 142, no. 4. https://doi.org/10.1053/j.gastro.2011.12.048
Huster D, Khne A, Bhattacharjee A, Raines L, Jantsch V, Noe J et al. Diverse functional properties of wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4). https://doi.org/10.1053/j.gastro.2011.12.048
Huster, Dominik ; Khne, Angelika ; Bhattacharjee, Ashima ; Raines, Lily ; Jantsch, Vanessa ; Noe, Johannes ; Schirrmeister, Wiebke ; Sommerer, Ines ; Sabri, Osama ; Berr, Frieder ; Mssner, Joachim ; Stieger, Bruno ; Caca, Karel ; Lutsenko, Svetlana. / Diverse functional properties of wilson disease ATP7B variants. In: Gastroenterology. 2012 ; Vol. 142, No. 4.
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AU - Noe, Johannes

AU - Schirrmeister, Wiebke

AU - Sommerer, Ines

AU - Sabri, Osama

AU - Berr, Frieder

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