Open AccessSynonymous mutation in adenosine triphosphatase copper‐transporting beta causes enhanced exon skipping in Wilson disease
Author(s) -
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,
JimenezHeredia Raul,
Weiss Karl Heinz,
Hahn Si Houn,
Janecke Andreas,
Ferenci Peter,
Zoller Heinz
Publication year - 2022
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1922
Subject(s) - exon , genetics , compound heterozygosity , triphosphatase , allele , biology , mutation , heterozygote advantage , single nucleotide polymorphism , gene , microbiology and biotechnology , genotype , guanosine
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.