TY  - JOUR
A1  - Höflich, Clemens
A1  - Brieger, Angela
A1  - Zeuzem, Stefan
A1  - Plotz, Guido
T1  - Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations
T2  - Scientific reports
N2  - 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.
KW  - Biochemistry
KW  - Gastroenterology
KW  - Genetics
KW  - Molecular biology
KW  - Pathogenesis
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63644
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-636449
SN  - 2045-2322
N1  - Open Access funding enabled and organized by Projekt DEAL.
VL  - 11.2021
SP  - 1
EP  - 10
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - [London]
ER  -