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临床和功能证据表明LRRK2 p.Arg1067Gln变异的致病性

Shen-Yang Lim^1,2, Tzi Shin Toh², Jia Wei Hor²

¹Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

NPJ Parkinson's disease

|February 23, 2025

概括

这种LRRK2 p.Arg1067Gln变种与东亚人口的帕金森病 (PD) 有关. 这项研究将其重新归类为致病性,而不是不确定性,原因是LRRK2激酶活性增加.

科学领域:

遗传学和神经学遗传学和神经学
神经退行性疾病神经退行性疾病

背景情况:

与LRRK2相关的帕金森病 (LRRK2-PD) 是一种常见的单一性帕金森病.
许多LRRK2变异仍然被归类为具有不确定的意义的变异 (VUS),特别是在代表性不足的人群中.

研究的目的:

为了研究LRRK2 p.Arg1067Gln变异的致病性.
根据新的遗传和功能数据重新分类LRRK2 p.Arg1067Gln变异.

主要方法:

来自马来西亚,新加坡和中国大陆的人口的大型帕金森病数据集的分析 (n=4901).
与对照组相比,基因关联测试用于确定东亚PD患者的变异丰富.
用于测量p.Arg1067Gln变异的LRRK2激酶活性的功能测试.

主要成果:

鉴定出12名中国血统患者患有LRRK2 p.Arg1067Gln变异,已知病例增加了100%以上.
在东亚PD患者中,p.Arg1067Gln变异显著丰富 (OR=8.0,95%CI:3.0-20.9).
与野生型相比,该变体的LRRK2激酶活性增加了约2倍,超过已知的致病性p.Gly2019Ser变体.

结论:

这种LRRK2 p.Arg1067Gln变异是致病的,并导致LRRK2-PD.
将p.Arg1067Gln从VUS重新归类为致病性是合理的.
这一发现对LRRK2-PD的遗传诊断和治疗策略有影响.

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