Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson's disease.

Autor: Stalke A; Department of Human Genetics, Hannover Medical School, Hannover, Germany.; Department of Pediatric Gastroenterology and Hepatology, Division of Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany., Behrendt A; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Hennig F; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Gohlke H; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Jülich, Germany., Buhl N; Department of Human Genetics, Hannover Medical School, Hannover, Germany.; Department of Pediatric Gastroenterology and Hepatology, Division of Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany., Reinkens T; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Baumann U; Department of Pediatric Gastroenterology and Hepatology, Division of Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany., Schlegelberger B; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Illig T; Hannover Unified Bank, Hannover Medical School, Hannover, Germany., Pfister ED; Department of Pediatric Gastroenterology and Hepatology, Division of Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany., Skawran B; Department of Human Genetics, Hannover Medical School, Hannover, Germany.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2023 Aug; Vol. 104 (2), pp. 174-185. Date of Electronic Publication: 2023 May 09.
DOI: 10.1111/cge.14352
Abstrakt: 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.
(© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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