Exploring the role of VAV2 rare variants in primary open-angle glaucoma: genetic insights and pathophysiological...

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^-6). 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.