Li Runze, Chen Yuhong, Zhang Shanshan, Ye Lin, Tian Huaping, Li Zheng, Wang Wentao, Li Hongjing, Liao Ruilin, Xu Haojue, Chuan Junlan, Qu Chao, Hao Fang, Jiang Dan, Zou Liang, Shi Yi, Yang Zhenglin, Huang Lulin
Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610075, China.
Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610075, China.
Sci China Life Sci. 2025 Aug 27. doi: 10.1007/s11427-024-2921-8.
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide, primarily due to the degeneration of retinal ganglion cells (RGCs). In this study, we reported vav guanine nucleotide exchange factor 2 (VAV2) as a POAG-associated gene. Through whole exome sequencing (WES) of 398 Han Chinese POAG patients and 2,010 controls, we discovered nine rare VAV2 variants linked to POAG (P_burden=1.40×l0). Functional analyses revealed that these variants disrupted normal VAV2 protein function, leading to compromised cytoskeletal organization in human trabecular meshwork cells and impaired axonal growth in the 661W cell line. In vivo, Vav2 knockout mice exhibited key POAG features, including increased intraocular pressure (IOP), abnormal trabecular meshwork structure, reduced visual sensitivity, and RGC loss. This study also implicated VAV2 in the modulation of the Rho signaling pathway, which is essential for maintaining trabecular meshwork integrity and neuronal function. Taken together, this research identified VAV2 as a candidate gene for POAG and suggests VAV2 as a potential target for genetic screening of POAG diagnostics.
原发性开角型青光眼（POAG）是全球不可逆性失明的主要原因，主要是由于视网膜神经节细胞（RGCs）的退化。在本研究中，我们报告了Vav鸟嘌呤核苷酸交换因子2（VAV2）作为一种与POAG相关的基因。通过对398例汉族POAG患者和2010例对照进行全外显子组测序（WES），我们发现了9种与POAG相关的罕见VAV2变异体（P_burden=1.40×10）。功能分析表明，这些变异体破坏了正常的VAV2蛋白功能，导致人小梁网细胞的细胞骨架组织受损以及661W细胞系中的轴突生长受损。在体内，Vav2基因敲除小鼠表现出关键的POAG特征，包括眼压（IOP）升高、小梁网结构异常、视觉敏感度降低和RGC损失。本研究还表明VAV2参与Rho信号通路的调节，这对于维持小梁网完整性和神经元功能至关重要。综上所述，本研究确定VAV2为POAG的候选基因，并提示VAV2作为POAG诊断基因筛查的潜在靶点。
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