TY  - JOUR
AU  - Stalke, Amelie
AU  - Behrendt, Annika
AU  - Hennig, Finja
AU  - Gohlke, Holger
AU  - Buhl, Nicole
AU  - Reinkens, Thea
AU  - Baumann, Ulrich
AU  - Schlegelberger, Brigitte
AU  - Illig, Thomas
AU  - Pfister, Eva-Doreen
AU  - Skawran, Britta
TI  - Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson's disease
JO  - Clinical genetics
VL  - 104
IS  - 2
SN  - 0009-9163
CY  - Malden, Mass.
PB  - Wiley
M1  - FZJ-2023-02415
SP  - 174-185
PY  - 2023
AB  - 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
LB  - PUB:(DE-HGF)16
C6  - 37157876
UR  - <Go to ISI:>//WOS:000985098200001
DO  - DOI:10.1111/cge.14352
UR  - https://juser.fz-juelich.de/record/1008582
ER  -