Duke Center for Neurodegeneration and Neurotherapeutics Research, Departments of Pharmacology and Cancer Biology, and Neurology, Duke University, Durham, NC 27710 USA.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Hum Mol Genet. 2021 Apr 30;30(6):454-466. doi: 10.1093/hmg/ddab058.
Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in LRRK2 and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic LRRK2 missense variants, we describe an online web-based resource that catalogs characteristics of over 1200 LRRK2 missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure-function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers (N = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the LRRK2 PD-risk variant rs76904798. These results provide a compendium of LRRK2 missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with LRRK2-linked PD.
通过家族性帕金森病 (PD) 的连锁分析，已经在富含亮氨酸重复激酶 2 (LRRK2) 基因中发现了致病性错义变异。随后，出现了其他对 PD 风险影响较小的错义变异，以及在全基因组关联研究中在 PD 病例中富集的非编码多态性（例如 rs76904798）。在这里，我们利用加速药物合作-帕金森病 (AMP-PD) 和基因组聚集 (gnomAD) 数据库中的最新全基因组序列，描述 LRRK2 中的新错义变体，并探索它们与已知致病性和 PD 相关的错义变体的关系。使用一种成功分类已知致病性 LRRK2 错义变体的计算预测工具，我们描述了一个在线网络资源，该资源记录了 1200 多个未知意义的 LRRK2 错义变体的特征。一些新的高致病性评分变体仅在 PD 病例中发现，它们紧密聚集在 ROC-COR-激酶结构域内。结构-功能预测支持其中一些变体对 LRRK2 激酶活性具有获得功能效应。在 AMP-PD 参与者中，所有 p.R1441G 携带者（N=89）也都是更常见的 PD 相关变体 p.M1646T 的携带者。此外，几乎所有携带 PD 相关 p.N2081D 错义变体的人也是 LRRK2 PD 风险变体 rs76904798 的携带者。这些结果提供了 LRRK2 错义变体及其相互关联的概要。虽然致病性 p.G2019S 变体是迄今为止最常见的高致病性评分变体，但我们的结果表明，超稀有错义变体可能会对增加携带 LRRK2 相关 PD 的个体数量产生重要的累积影响。
