Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S23-8. doi: 10.1016/S1353-8020(13)70009-9.
In the past 15 years there has been substantial progress in our understanding of the genetics of Parkinson's disease (PD). Highly-penetrant mutations in different genes (SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1) are known to cause rare monogenic forms of the disease. Furthermore, different variants with incomplete penetrance in the LRRK2 and the GBA gene are strong risk factors for PD, and are especially prevalent in some populations. Last, common variants of small effect size, modulating the risk for PD, have been identified by genome-wide association studies in more than 20 chromosomal loci. Here, I first outline the evolution of the research strategies to find PD-related genes, and then focus on recent advances in the field of the monogenic forms, including VPS35 mutations in autosomal dominant PD, and DNAJC6 and SYNJ1 mutations in recessive forms of juvenile parkinsonism. Additional genetic determinants of PD likely remain to be identified, as the currently known mutations and variants only explain a minor fraction of the disease burden. There is great expectation that the new DNA sequencing technologies (exome and whole-genome sequencing) will bring us closer to the full resolution of the genetic landscape of PD.
在过去的 15 年中，我们对帕金森病（PD）遗传学的理解取得了实质性进展。不同基因（SNCA、LRRK2、VPS35、Parkin、PINK1 和 DJ-1）中的高外显率突变已知会导致罕见的单基因形式的疾病。此外，LRRK2 和 GBA 基因中的不完全外显变体是 PD 的强风险因素，尤其在某些人群中更为普遍。最后，通过全基因组关联研究在 20 多个染色体位置上确定了具有小效应大小的调节 PD 风险的常见变体。在这里，我首先概述了寻找 PD 相关基因的研究策略的演变，然后重点介绍单基因形式领域的最新进展，包括常染色体显性 PD 中的 VPS35 突变，以及少年型帕金森病的隐性形式中的 DNAJC6 和 SYNJ1 突变。可能还有其他 PD 的遗传决定因素有待确定，因为目前已知的突变和变体仅解释了疾病负担的一小部分。人们非常期望新的 DNA 测序技术（外显子组和全基因组测序）将使我们更接近 PD 遗传景观的完全解析。
