Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

  • Pathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.

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Author:Clemens Höflich, Angela BriegerORCiDGND, Stefan ZeuzemORCiDGND, Guido PlotzORCiDGND
URN:urn:nbn:de:hebis:30:3-636449
DOI:https://doi.org/10.1038/s41598-021-87000-9
ISSN:2045-2322
Parent Title (English):Scientific reports
Publisher:Macmillan Publishers Limited, part of Springer Nature
Place of publication:[London]
Document Type:Article
Language:English
Date of Publication (online):2021/04/07
Date of first Publication:2021/04/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/08/23
Tag:Biochemistry; Gastroenterology; Genetics; Molecular biology; Pathogenesis
Volume:11.2021
Article Number:7674
Page Number:10
First Page:1
Last Page:10
Note:
Open Access funding enabled and organized by Projekt DEAL.
HeBIS-PPN:505166054
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0