Trinh Joanne, Schymanski Emma L, Smajic Semra, Kasten Meike, Sammler Esther, Grünewald Anne
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Med Genet. 2022 Aug 12;34(2):103-116. doi: 10.1515/medgen-2022-2127. eCollection 2022 Jun.
Mutations in () are the most frequent cause of dominantly inherited Parkinson's disease (PD). mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of -PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of -PD. In this article, we (i) describe the clinical characteristics of mutation carriers, (ii) review known genes linked to -PD onset and (iii) summarize the cellular functions of with particular emphasis on potential penetrance-related molecular mechanisms. This section covers 's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future , and studies that could provide a better understanding of the processes triggering PD in individuals with mutations.
（）基因的突变是常染色体显性遗传帕金森病（PD）最常见的病因。突变中，p.G2019S最为常见，其遗传具有较低的外显率。有趣的是，与G2019S相关的疾病风险会因携带者的种族背景而有显著差异。虽然这表明在定义 -PD外显率方面存在遗传因素，但仅有少数变体被证明可改变携带突变患者的发病年龄，目前控制从健康状态转变为患病状态的确切细胞途径仍不清楚。鉴于这一知识空白，最近的研究也探讨了环境和生活方式因素作为 -PD潜在的修饰因素。在本文中，我们（i）描述突变携带者的临床特征，（ii）回顾与 -PD发病相关的已知基因，（iii）总结的细胞功能，特别强调与潜在外显率相关的分子机制。本节涵盖在Rab GTP酶和免疫信号传导以及线粒体稳态和动力学调节中的作用。此外，我们还探讨了关于（iv）生活方式和（v）可能影响突变外显率的环境因素的文献，以期进行进一步的暴露组学研究。最后，基于这一全面概述，我们提出了未来潜在的、和研究，这些研究可能会更好地理解在携带突变的个体中引发PD的过程。
