GPR97 variants and their influence on pathological myopia: implications for glucocorticoid treatment

Qi Zhao, Zhaoxia Mu, Huihui Gu, Wei Cheng, Yulian Xu, Yingying Jiang, Geping Wu, Lijun Pu

Abstract


Background and purpose: Pathologic myopia (PM) is a severe form of myopia associated with structural changes in the eye, leading to vision impairment. Identifying genetic factors that contribute to PM can enhance the treatment of the condition. This study aimed to investigate the association between the GPR97 and PM and to evaluate the impact of glucocorticoid treatment on PM.

Experimental approach: A cohort of 412 sporadic PM patients underwent Sanger sequencing and genotyping for GPR97 gene variants. Thirty-one PM patients with various GPR97 genotypes received glucocorticoid and brinzolamide treatment over 24 months. Real-time PCR was employed to examine the target gene mRNA expression. A scratch assay was performed to detect cell migration ability.

Findings/Results: A significant association was identified between GPR97 rs76688596 genotypes and PM occurrence. The CC genotype was linked to elevated intraocular pressure (IOP). In human scleral fibroblasts, overexpression of GPR97 Arg396 resulted in upregulation of IOP-related genes serine/arginine-rich splicing factor 3, peptidyl-prolyl cis-trans isomerase 4, peptidyl-prolyl cis-trans isomerase 5, and nuclear receptor subfamily 3 group C member 1. The GPR97 Arg396 mutation inhibited the glucocorticoid-GPR97 axis and reduced cell migration ability. Clinically, CC genotype carriers exhibited significant improvements in axial length, spherical equivalent, IOP, best-corrected visual acuity, and visual field mean sensitivity with glucocorticoid treatment.

Conclusion and implications: The study revealed that the GPR97 rs76688596 G > C variant is associated with PM pathogenesis, influencing gene expression related to IOP. The differential response to glucocorticoid treatment among GPR97 genotypes suggests personalized therapeutic potential.

 


Keywords


Glucocorticoid treatment; GPR97; Intraocular pressure; Pathologic myopia.

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References


Ohno-Matsui K, Wu PC, Yamashiro K, Vutipongsatorn K, Fang Y, Cheung CMG, et al. IMI pathologic myopia. Invest Ophthalmol Vis Sci. 2021;62(5):5,1-36.DOI: 10.1167/iovs.62.5.5.

Chu R, Ni P, Ni M, Shen F. Genetic epidemiology study of pathological myopia. Chin J Med Gen. 2000;17(3):178-180.PMID: 10837519.

Zhu G, Hewitt AW, Ruddle JB, Kearns LS, Brown SA, Mackinnon JR, et al. Genetic dissection of myopia: evidence for linkage of ocular axial length to chromosome 5q. Ophthalmology. 2008;115(6):1053-1057.DOI: 10.1016/j.ophtha.2007.08.013.

Ratnamala U, Lyle R, Rawal R, Singh R, Vishnupriya S, Himabindu P, et al. Refinement of the X-linked nonsyndromic high-grade myopia locus MYP1 on Xq28 and exclusion of 13 known positional candidate genes by direct sequencing. Invest Ophthalmol Vis Sci. 2011;52(9):6814-6819.DOI: 10.1167/iovs.10-6815.

Zhao YY, Zhang FJ, Zhu SQ, Duan H, Li Y, Zhou ZJ, et al. The association of a single nucleotide polymorphism in the promoter region of the LAMA1 gene with susceptibility to Chinese high myopia. Mol Visi. 2011;17:1003-1010.PMID: 21541277.

Deng ZJ, Shi KQ, Song YJ, Fang YX, Wu J, Li G, et al. Association between a lumican promoter polymorphism and high myopia in the Chinese population: a meta-analysis of case-control studies. Ophthalmologica. 2014;232(2):110-117.DOI: 10.1159/000356698.

Siwko S, Lai L, Weng J, Liu M. Lgr4 in ocular development and glaucoma. J Ophthalmol. 2013;2013:987494,1-9.DOI: 10.1155/2013/987494.

Reyes-Resina I, Awad Alkozi H, Del Ser-Badia A, Sanchez-Naves J, Lillo J, Jimenez J, et al. Expression of melatonin and dopamine D3 receptor heteromers in eye ciliary body epithelial cells and negative correlation with ocular hypertension. Cells. 2020;9(1):152,1-20.DOI: 10.3390/cells9010152.

Patel N, Itakura T, Gonzalez Jr, Schwartz SG, Fini ME. GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid-stimulated expression and novel nuclear role. PLoS One. 2013;8(2):e57843,1-16.DOI: 10.1371/journal.pone.0057843.

Ping YQ, Mao C, Xiao P, Zhao RJ, Jiang Y, Yang Z, et al. Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex. Nature. 2021;589(7843):620-626.DOI: 10.1038/s41586-020-03083-w.

Valtcheva N, Primorac A, Jurisic G, Hollmen M, Detmar M. The orphan adhesion G protein-coupled receptor GPR97 regulates migration of lymphatic endothelial cells via the small GTPases RhoA and Cdc42. J Biol Chem. 2013;288(50):35736-35748.DOI: 10.1074/jbc.M113.512954.

Zhang H, Chu G, Wang G, Yao M, Lu S, Chen T. Mechanistic understanding of the palmitoylation of G(o) protein in the allosteric regulation of adhesion receptor GPR97. Pharmaceutics. 2022;14(9):1-16.DOI: 10.3390/pharmaceutics14091856.

Wei WB, Dong L. Paying attention to the fundus complications and improving the prevention and treatment of pathological myopia. Chin J Ophthalmol. 2021;57(6):401-405.DOI: 10.3760/cma.j.cn112142-20210114-00035.

Bermudez JY, Webber HC, Brown B, Braun TA, Clark AF, Mao W. A Comparison of gene expression profiles between glucocorticoid responder and non-responder bovine trabecular meshwork cells using RNA sequencing. PLoS One. 2017;12(1):e0169671,1-20.DOI: 10.1371/journal.pone.0169671.

Rufer F, Uthoff D. [Symptoms and therapy for steroid glaucoma]. Klin Monbl Augenheilkd. 2013;230(7):692-696.DOI: 10.1055/s-0032-1328472.

Urban RC Jr, Dreyer EB. Corticosteroid-induced glaucoma. Int Ophthalmol Clin. 1993;33(2):135-139.DOI: 10.1097/00004397-199303320-00013.

Zode GS, Sharma AB, Lin X, Searby CC, Bugge K, Kim GH, et al. Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. J Clin Invest. 2014;124(5):1956-1965.DOI: 10.1172/JCI69774.

Qiu C, Chen M, Yao J, Sun X, Xu J, Zhang R, et al. Mechanical strain induces distinct human scleral fibroblast lineages: differential roles in cell proliferation, apoptosis, migration, and differentiation. Invest Ophthalmol Vis Sci. 2018;59(6):2401-2410.DOI: 10.1167/iovs.18-23855.

Gentle A, Liu Y, Martin JE, Conti GL, McBrien NA. Collagen gene expression and the altered accumulation of scleral collagen during the development of high myopia. J Biol Chem. 2003;278(19):16587-16594.DOI: 10.1074/jbc.M300970200.

Lam DS, Lee WS, Leung YF, Tam PO, Fan DS, Fan BJ, et al. TGFbeta-induced factor: a candidate gene for high myopia. Invest Ophthalmol Vis Sci. 2003;44(3):1012-1015.DOI: 10.1167/iovs.02-0058.

Inamori Y, Ota M, Inoko H, Okada E, Nishizaki R, Shiota T, et al. The COL1A1 gene and high myopia susceptibility in Japanese. Hum Genet. 2007;122(2):151-157.DOI: 10.1007/s00439-007-0388-1.

Harper AR, Summers JA. The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development. Exp Eye Res. 2015;133:100-111.DOI: 10.1016/j.exer.2014.07.015.

Li M, Luo Z, Yan X, Chen Z. The anterior segment biometrics in high myopia eyes. Ophthalmic Res. 2023;66(1):75-85.DOI: 10.1159/000526280.

Metlapally R, Li YJ, Tran-Viet KN, Abbott D, Czaja GR, Malecaze F, et al. COL1A1 and COL2A1 genes and myopia susceptibility: evidence of association and suggestive linkage to the COL2A1 locus. Invest Ophthalmol Vis Sci. 2009;50(9):4080-4086.DOI: 10.1167/iovs.08-3346.

Dibas A, Yorio T. Glucocorticoid therapy and ocular hypertension. Eur J Pharmacol. 2016;787:57-71.DOI: 10.1016/j.ejphar.2016.06.018.

Wang XQ, Duan ZX, He XG, Zhou XY. Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoid-induced ocular hypertension and primary open angle glaucoma. Int J Ophthalmol. 2015;8(1):169-173.DOI: 10.3980/j.issn.2222-3959.2015.01.30.

Zhou X, Ye C, Wang X, Zhou W, Reinach P, Qu J. Choroidal blood perfusion as a potential "rapid predictive index" for myopia development and progression. Eye Vis. 2021;8(1):1,1-5.DOI: 10.1186/s40662-020-00224-0.

Chen W, Zhao B, Jiang R, Zhang R, Wang Y, Wu H, et al. Cytokine expression profile in aqueous humor and sera of patients with acute anterior uveitis. Curr Mol Med. 2015;15(6):543-549.

DOI: 10.2174/1566524015666150731100012.

Wang P, Chen S, Liu Y, Lin F, Song Y, Li T, et al. Lowering intraocular pressure: a potential approach for controlling high myopia progression. Invest Ophthalmol Vis Sci. 2021;62(14):17,1-6.DOI: 10.1167/iovs.62.14.17.


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