Synonymous mutation in adenosine triphosphatase copper‐transporting beta causes enhanced exon skipping in Wilson disease. Issue 7 (10th March 2022)

• Record Type: Journal Article
• Authors: Panzer, Marlene; Viveiros, André; Schaefer, Benedikt; Baumgartner, Nadja; Seppi, Klaus; Djamshidian, Atbin; Todorov, Theodor; Griffiths, William J. H.; Schott, Eckart; Schuelke, Markus; Eurich, Dennis; Stättermayer, Albert Friedrich; Bomford, Adrian; Foskett, Pierre; Vodopiutz, Julia; Stauber, Rudolf; Pertler, Elke; Morell, Bernhard; Tilg, Herbert; Müller, Thomas; Kiechl, Stefan; Jimenez‐Heredia, Raul; Weiss, Karl Heinz; Hahn, Si Houn; Janecke, Andreas; Ferenci, Peter; Zoller, Heinz
• Is Part Of: Hepatology communications. Volume 6:Issue 7(2022)
• Page Start: 1611
• Page End: 1619
• Publication Date: 2022-03-10
• Subjects: Hepatology -- Periodicals; Liver -- Diseases -- Periodicals; Liver Diseases; Gastroenterology; Periodicals; Fulltext; Internet Resources; Periodicals; 616.36
• DOI: 10.1002/hep4.1922
• Languages: English
• ISSNs: 2471-254X

Abstract

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. Abstract : Wilson disease is caused by recessive pathogenic variants in ATP7B. In a subgroup of patients no or only one genetic defect can be identified. The present study shows that one in 100 patients with WD have a synonymous (silent) genetic variant, which had not been previously recognized as disease‐causing. This variant causes alternative splicing resulting, predicted to result in an in‐frame deletion of 78 residues of the ATP7B protein.image