Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.
Authors
Baumgartner, Nadja
Foskett, Pierre
Hahn, Si Houn
Janecke, Andreas
Publication Date
2022-07Journal Title
Hepatol Commun
ISSN
2471-254X
Publisher
Ovid Technologies (Wolters Kluwer Health)
Language
en
Type
Article
This Version
AO
VoR
Metadata
Show full item recordCitation
Panzer, M., Viveiros, A., Schaefer, B., Baumgartner, N., Seppi, K., Djamshidian, A., Todorov, T., et al. (2022). Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.. Hepatol Commun https://doi.org/10.1002/hep4.1922
Description
Funder: Österreichische Forschungsförderungsgesellschaft; Id: http://dx.doi.org/10.13039/501100004955
Funder: Verein zur Foerderung der Wissenschaft in Gastroenterologie & Hepatologie
Funder: Christian Doppler Forschungsgesellschaft; Id: http://dx.doi.org/10.13039/501100006012
Abstract
Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10-6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10-5 ; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.
Keywords
ORIGINAL ARTICLE, ORIGINAL ARTICLES
Identifiers
hep41922
External DOI: https://doi.org/10.1002/hep4.1922
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334856
Rights
Licence:
http://creativecommons.org/licenses/by-nc-nd/4.0/
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