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

Abstract 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...

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Autores principales:	Clemens Höflich, Angela Brieger, Stefan Zeuzem, Guido Plotz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2df93a0a50b94902ad043546d5a053b7
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spelling	oai:doaj.org-article:2df93a0a50b94902ad043546d5a053b72021-12-02T18:15:45ZInvestigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations10.1038/s41598-021-87000-92045-2322https://doaj.org/article/2df93a0a50b94902ad043546d5a053b72021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87000-9https://doaj.org/toc/2045-2322Abstract 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.Clemens HöflichAngela BriegerStefan ZeuzemGuido PlotzNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Clemens Höflich Angela Brieger Stefan Zeuzem Guido Plotz Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
description	Abstract 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.
format	article
author	Clemens Höflich Angela Brieger Stefan Zeuzem Guido Plotz
author_facet	Clemens Höflich Angela Brieger Stefan Zeuzem Guido Plotz
author_sort	Clemens Höflich
title	Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
title_short	Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
title_full	Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
title_fullStr	Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
title_full_unstemmed	Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
title_sort	investigation of the wilson gene atp7b transcriptional start site and the effect of core promoter alterations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2df93a0a50b94902ad043546d5a053b7
work_keys_str_mv	AT clemenshoflich investigationofthewilsongeneatp7btranscriptionalstartsiteandtheeffectofcorepromoteralterations AT angelabrieger investigationofthewilsongeneatp7btranscriptionalstartsiteandtheeffectofcorepromoteralterations AT stefanzeuzem investigationofthewilsongeneatp7btranscriptionalstartsiteandtheeffectofcorepromoteralterations AT guidoplotz investigationofthewilsongeneatp7btranscriptionalstartsiteandtheeffectofcorepromoteralterations
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Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

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