Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Panzer, M; Viveiros, A; Schaefer, B; Baumgartner, N; Seppi, K; Djamshidian, A; Todorov, T; Griffiths, WJH; Schott, E; Schuelke, M; Eurich, D; Stattermayer, AF; Bomford, A; Foskett, P; Vodopiutz, J; Stauber, R; Pertler, E; Morell, B; Tilg, H; Muller, T; Kiechl, S; Jimenez-Heredia, R; Weiss, KH; Hahn, SH; Janecke, A; Ferenci, P; Zoller, H.
Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease
HEPATOL COMMUN. 2022;
Doi: 10.1002/hep4.1922
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- Co-Autor*innen der Med Uni Graz
- Stauber Rudolf
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- 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 x 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.