Background. LRRK2 mutations have emerged as the most prevalent and potentially treatable determinants of Parkinson’s disease (PD). Peculiar geographic distribution of these mutations has triggered an interest in genotyping PD cohorts of different ethnic backgrounds for LRRK. Objective. Here, we report on the results of LRRK2 screening in the first Central Asian PD cohort. Methods. 246 PD patients were consecutively recruited by movement disorder specialists from four medical centers in Kazakhstan, and clinicodemographic data and genomic DNA from blood were systematically obtained and shipped to the Institute of Neurology University College London together with DNAs from 200 healthy controls. The cohort was genotyped for five LRRK2 mutations (p.Gly2019Ser, p.Arg1441His, p.Tyr1699Cys, p.Ile2020Thr, and p.Asn1437His) and three East Asian disease-associated variants (p.Gly2385Arg, p.Ala419Val, and p.Arg1628Pro) via Kompetitive allele-specific polymerase chain reaction assay analysis. Results. None of the study subjects carried LRRK2 mutations, whereas the following Asian variants were found with insignificant odds ratios (OR): p.Gly2385Arg (1.2%, minor allele frequency (MAF) 0.007, OR 1.25, ), p.Ala419Val (3.7%, MAF 0.02, OR 1.5, ), and p.Arg1628Pro was found only in 1% of controls. p.Gly2385Arg was positive in a big family with PD and tremor, although with incomplete segregation. One early-onset PD subject was homozygous for p.Ala419Val who developed fast progression and severe dyskinesias. p.Ala419Val was associated with early-onset PD. Conclusions. We showed that East Asian LRRK variants could be found in Central Asian populations but their pathogenicity remains to be elucidated in larger PD cohorts.

中文翻译：

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哈萨克斯坦第一批帕金森病队列中的 LRRK2 突变和亚洲疾病相关变异


背景。 LRRK2 突变已成为帕金森病 (PD) 最普遍且可能可治疗的决定因素。这些突变的特殊地理分布引发了人们对不同种族背景的 PD 队列进行 LRRK 基因分型的兴趣。客观的。在这里，我们报告了第一个中亚 PD 队列中 LRRK2 筛查的结果。方法。哈萨克斯坦四个医疗中心的运动障碍专家连续招募了 246 名 PD 患者，系统地获取了临床人口统计学数据和血液基因组 DNA，并与 200 名健康对照者的 DNA 一起运送到伦敦大学学院神经病学研究所。该队列针对五个 LRRK2 突变（p.Gly2019Ser、p.Arg1441His、p.Tyr1699Cys、p.Ile2020Thr 和 p.Asn1437His）和三个东亚疾病相关变异（p.Gly2385Arg、p.Ala419Val 和 p.Ala419Val）进行了基因分型。 Arg1628Pro）通过竞争性等位基因特异性聚合酶链反应测定分析。结果。研究对象均未携带 LRRK2 突变，而以下亚洲变异的优势比 (OR) 不显着：p.Gly2385Arg（1.2%，次要等位基因频率 (MAF) 0.007，OR 1.25， ）， p.Ala419Val（3.7%，MAF 0.02，OR 1.5， ），而 p.Arg1628Pro 仅在 1% 的对照中发现。 p.Gly2385Arg 在患有 PD 和震颤的大家族中呈阳性，尽管分离不完全。一名早发性 PD 受试者的 p 是纯合的。Ala419Val 出现快速进展和严重运动障碍。 p.Ala419Val 与早发性 PD 相关。结论。我们发现东亚 LRRK 变异可以在中亚人群中发现，但其致病性仍有待在更大的 PD 人群中阐明。