Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
07 04 2021
07 04 2021
Historique:
received:
05
01
2021
accepted:
22
03
2021
entrez:
8
4
2021
pubmed:
9
4
2021
medline:
11
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33828154
doi: 10.1038/s41598-021-87000-9
pii: 10.1038/s41598-021-87000-9
pmc: PMC8027023
doi:
Substances chimiques
Copper
789U1901C5
Ceruloplasmin
EC 1.16.3.1
ATP7B protein, human
EC 7.2.2.8
Copper-Transporting ATPases
EC 7.2.2.8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7674Références
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