Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence.
Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence.
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DOI：
10.1016/j.livres.2017.08.003
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Medici V
中科院分区：
文献类型：
--
作者：
Kieffer DA;Medici V
环境因素，包括饮食、运动、压力和毒素，深刻影响疾病表型。这篇综述探讨了威尔逊病（WD），一种常染色体隐性遗传疾病，如何受到遗传和环境输入的影响。 WD 是由铜转运蛋白基因 ATP7B 突变引起的，导致铜在肝脏和大脑中积累，导致肝脏、神经和精神症状。这些症状的严重程度各不相同，最早可能在幼儿期到老年之间的任何时间出现。 ATP7B 中已鉴定出 300 多种致病突变，但将基因型与表型表现联系起来的尝试却收效甚微，这促使研究人员寻找替代机制（例如表观遗传学）来解释高度多样化的临床表现。此外，WD 还伴有线粒体的结构和功能异常，可能会改变基因表达表观遗传调控所需的代谢物的产生。值得注意的是，环境暴露会影响基因表达和线粒体功能的调节。我们提出了 WD 进展的“多重打击”假说，该假说认为最初的打击是影响胎儿基因表达和表观遗传机制的环境因素，随后的“打击”是后代出生后发生的环境暴露。这些环境影响和随后的表观遗传调控变化可能会影响铜的积累并最终影响 WD 表型。生活方式的改变，包括饮食、增加体力活动、减轻压力和避免毒素，可能会影响 WD 的表现和病程，因此可以作为潜在的辅助或替代疗法。
Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.