Potential Involvements of Anterior Segment Dysgenesis-Associated Genes in Primary Congenital Glaucoma

Background: The anterior segment of the eye plays a crucial role in maintaining the normal intraocular pressure and vision. Developmental defects in the anterior segment structures lead to anterior segment dysgenesis (ASD) and primary congenital glaucoma (PCG), which share overlapping clinical features. Several genes have been mapped and characterized in ASD, some of which are also involved in other glaucoma phenotypes. PCG exhibits genetic heterogeneity like ASD, but the known genes do not account for the entire genetic basis of the disease. Considering the significant phenotypic and genotypic overlap between ASD and PCG, this article explores the possible involvements of ASD-associated genes in PCG pathogenesis.

Methods: A nonsystematic search in PubMed was performed using various combinations of keywords related to ASD, glaucoma, genetics, and molecular mechanisms, and articles published up until March 2024 were considered. Specifically, information pertaining to ASD-associated genes (FBN1, FOXE3, HMX1, LMX1B, MAF, OTX2, PAX6, PITX2, PITX3, PRDM5, PRSS56, RAX, SLC4A11, SOX2, TRIM44, VAX1, and WT1) was extracted, and their expressions were determined from the GTEx and EMBL-EBI Expression Atlas. Interactions of these genes were determined through the Ingenuity Pathway Analysis software.

Results: Most of the ASD-associated genes were found to be highly expressed in the early embryonic stages. Interactome analysis revealed that TRIM44, PAX6, WT1, SOX2, OTX2, PRDM5, and FBN1 interacted through the NFκB and Akt/PI3K pathways, either directly, or through interactions with other partners. FOXC1, PITX2, and HMX1 interacted through Wnt and Hedgehog signaling pathways. Both ASD and PCG present similar clinical features and harbor mutations in genes that are implicated in both these conditions. Collectively, we constructed a hypothetical model and proposed two parallel mechanisms comprising the defects in the anterior chamber angle and cell death in PCG pathogenesis.

Conclusions: Our findings suggest that complex interplay of these ASD-associated genes and their interactions could potentially result in defects in the anterior chamber angle and trabecular meshwork and induce cell death, resulting in PCG pathogenesis.