Biomedical Research Laboratory, 1st Department of Internal Medicine, University Hospital, Frankfurt, Germany.
Medizinische Klinik 1, Biomedizinisches Forschungslabor, Haus 11, Universitätsklinik Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
Sci Rep. 2021 Apr 7;11(1):7674. doi: 10.1038/s41598-021-87000-9.
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.
ATP7B 基因中的致病遗传变异导致威尔逊病，这是一种铜代谢的隐性疾病，其临床表现具有显著的变异性。启动子突变很少被报道，转录起始位点（核心启动子）的存在存在争议。我们定量研究了转录起始，发现它位于翻译起始的附近。人类核心启动子中保守碱基的单核苷酸改变对转录活性的影响是适度的，这解释了为什么核心启动子内明显的致病性突变尚未被报道。此外，核心启动子包含两个常见的多态性（rs148013251 和 rs2277448），可能导致不完全失活突变的威尔逊病患者表型变异性。然而，这两种多态性都没有显著调节体外 ATP7B 的表达，也没有影响健康个体的铜家庭参数。总之，这些研究确定了 ATP7B 转录起始的生物学相关位点，并表明该位点的遗传变异虽然是转录活性的焦点，但对威尔逊病的发病机制没有显著贡献。
