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• W4308709098 abstract "Abstract MYOC mutations are the leading genetic causes of primary open-angle glaucoma (POAG). We previously identified a recurrent Gly367Arg mutant myocilin (MYOC/p.G367R) associated with juvenile open-angle glaucoma (JOAG) in a large Chinese family, but the pathogenic mechanism remains unclear. The MYOC/p.G367R carrier presented a high intraocular pressure and typic POAG phenotype, including an open anterior angle, a thinning retina nerve fiber layer, and a tubular visual field. Trabecular meshwork (TM) cell lines (iHTMCs) and primary TM cells (pHTMCs) expressing wild-type or mutant (G367R) myocilin were constructed to further verify the disease-causing roles of MYOC/p.G367R mutation in the TM. The G367R mutant had no effect on cytoskeletal arrangement or fibronectin production. Consistently, the combination of G367R-myocilin with the chaperones Grp94 and CRYAB impaired the intracellular degradation mechanism and caused aggregation of myocilin in the ER. The excessive accumulation of mutated myocilin in the ER resulted in chronic ER stress, and apoptosis. Moreover, autophagy plays an essential role in regulating the pathogenesis of MYOC mutations. Rapamycin activated autophagy and decreased intracellular myocilin accumulation. Chloroquine inhibited autophagy and promoted intracellular myocilin retention, exacerbating ER stress and oxidative stress in TM cells. Meanwhile, the retinal cell line 661W was used to study the effect of MYOC/p.G367R mutation in retinal cells. Similar to TM cells, the autophagic activity of 661W cells expressing G367R-myocilin was inhibited. In addition, MYOC/p.G367R mutation induced mitochondrial dysfunction and promoted superoxide onion generation in 661W cells. Together, our findings suggest that G367R mutant myocilin induces cell dysfunction of the TM and retina through excessive intracellular accumulation of mutant myocilin caused by impairment of protein clearance mechanisms. Furthermore, autophagy may serve as a therapeutic target to promote the degradation of mutant myocilin and alleviate cell dysfunction." @default.
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• W4308709098 date "2022-11-10" @default.
• W4308709098 modified "2023-10-16" @default.
• W4308709098 title "MYOC/p.G367R mutation induces cell dysfunction of the trabecular meshwork and retina via impairment of the protein degradation mechanism" @default.
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• W4308709098 doi "https://doi.org/10.21203/rs.3.rs-2206470/v1" @default.
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