Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.
Hahn, Si Houn
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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
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
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.
ORIGINAL ARTICLE, ORIGINAL ARTICLES
External DOI: https://doi.org/10.1002/hep4.1922
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334856