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 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.

TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells

“…This might be due to the effect of the so-called “homotypic cluster”, a group of adjacent binding sites for the same transcription factor [ 36 ]. Such homotypic clusters usually reside in bidirectional promoters, like this of ATP7B , which shares more than 1 kb bidirectional promoter with the ALG11 gene [ 37 ] and might slow down the kinetics of the transcription process compared to a promotor region with a single binding site [ 36 ].…”