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Functional Genomic Analysis of Glaucoma Pathogenesis Due to gmds Mutation in Zebrafish

ABSTRACT: Glaucoma, a major cause of irreversible blindness, is characterized by optic nerve damage and loss of retinal ganglion cells (RGC). SNPs in the GDP-MANNOSE 4,6-DEHYDRATASE (GMDS) gene have been linked to primary open-angle glaucoma (POAG) and treatment responses. The GMDS gene plays a critical role in fucosylation, a process essential for modifying glycoproteins and glycolipids, yet no mechanism for its role in glaucoma pathology has been described. Our study investigates the effects of gmds haploinsufficiency using a CRISPR/Cas9 induced mutation in zebrafish. RNA sequencing (RNAseq) analysis shows significant downregulation of stress response genes including those of the crystallin family, and increased expression of cell death genes in gmds heterozygous mutant eyes. These gene expression changes correlate with phenotypic alterations, including RGC layer thinning, RGC loss, and reduced optic nerve head width in adult gmds heterozygotes relative to wild type siblings. Our findings provide new insights into the role of GMDS in regulating eye function and suggests that GMDS may influence glaucoma risk by regulating the response to stress. This study provides a layer of functional evidence supporting the predictions made by previous GWAS findings, enhancing our understanding of the genetic basis of glaucoma. It highlights the potential of GMDS as a therapeutic target for mitigating glaucoma-related vision loss, opening new avenues for glaucoma research and treatment development.

ORGANISM(S): Danio rerio

PROVIDER: GSE281042 | GEO | 2025/06/24

REPOSITORIES: GEO

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Project description:Purpose: Marked extracellular matrix (ECM) remodeling occurs in the human optic nerve head in primary open angle glaucoma (POAG). The glial fibrillary acid protein (GFAP) negative lamina cribrosa cell may play an important role in this remodeling process. The authors report the first study of global and ECM-focused gene transcription differentials between GFAP-negative negative lamina cribrosa (LC) cells from normal and POAG human donors. Methods: GFAP-negative LC cell lines were generated from the optic nerve tissue of three normal (n=3) and three POAG (n=3) human donors. Using Affymetrix U133A arrays the transcriptional profile between the normal and diseased groups were compared. Bioinformatic analysis was carried out using robust multichip average (RMA Express) and EASE/David. Real time TaqMan PCR and immunohistochemistry analyses were performed to validate the microarray data. Results: 285 genes were up regulated by greater than 1.5 fold and 413 were down regulated by greater than 1.5 fold in the POAG LC cells versus normal controls. Upregulated genes in POAG LC cells included, SPARC, periostin, thrombospondin, CRTL-1, CTGF and collagen types I, III, V and VIII. Downregulated ECM genes in POAG included MMP-1, fibulin, decorin and tenacsin XB. All TaqMan PCR validation assays were significant (*p<0.05) and consistent with the array data. Immunohistochemistry of one target (periostin) confirmed its differential expression at the protein level in POAG optic nerve head tissue compared with non-glaucomatous controls. Functional annotation and over-representation analysis identified ECM genes as a statistically over-represented class of genes in POAG LC cells compared with normal LC cells. Conclusions: This study reports for the first time that POAG LC cells in-vitro demonstrate up regulated ECM and pro-fibrotic gene expression compared with normal LC cells. This may be a pathological characteristic of this cell type in POAG in-vivo. We believe that the LC cell may be a pivotal regulator of optic nerve head ECM remodeling and an attractive target for future therapeutic strategies in POAG.

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Functional Genomic Analysis of Glaucoma Pathogenesis Due to gmds Mutation in Zebrafish

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