Journal Article

FZJ-2023-02415

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson's disease

Stalke, A. (Corresponding author) ; Behrendt, A. ; Hennig, F. ; Gohlke, H.FZJ* ; Buhl, N. ; Reinkens, T. ; Baumann, U. ; Schlegelberger, B. ; Illig, T. ; Pfister, E.-D. ; Skawran, B.

2023
Wiley Malden, Mass.

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Please use a persistent id in citations: doi:10.1111/cge.14352  doi:10.34734/FZJ-2023-02415

Abstract: Wilson's disease (WD, MIM#277900) is an autosomal recessive disorder resulting in copper excess caused by biallelic variants in the ATP7B gene (MIM#606882) encoding a copper transporting P-type ATPase. ATP7B variants of unknown significance (VUS) are detected frequently, sometimes impeding a clear diagnosis. Functional analyses can help to classify these variants as benign or pathogenic. Additionally, variants already classified as (likely) pathogenic benefit from functional analyses to understand their pathomechanism, thus contribute to the development of personalized treatment approaches in the future. We described clinical features of six WD patients and functionally characterized five ATP7B missense variants (two VUS, three yet uncharacterized likely pathogenic variants), detected in these patients. We determined the protein level, copper export capacity, and cellular localization in an in vitro model and potential structural consequences using an ATP7B protein model based on AlphaFold. Our analyses give insight into the pathomechanism and allowed reclassification for the two VUS to likely pathogenic and for two of the three likely pathogenic variants to pathogenic

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Contributing Institute(s):

1. Bioinformatik (IBG-4)

Research Program(s):

1. 2171 - Biological and environmental resources for sustainable use (POF4-217) (POF4-217)
2. DFG project 433387263 - Next-Generation Sequencing und funktionelle Charakterisierung von Varianten unklarer Signifikanz in pädiatrischen Hepatopathien (433387263) (433387263)

Appears in the scientific report 2023

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