Glaucoma Genes and Mechanisms

Abstract

Genetic studies have yielded important genes contributing to both early-onset and adult-onset forms of glaucoma. The proteins encoded by the current collection of glaucoma genes participate in a broad range of cellular processes and biological systems. Approximately half the glaucoma-related genes function in the extracellular matrix, however proteins involved in cytokine signaling, lipid metabolism, membrane biology, regulation of cell division, autophagy, and ocular development also contribute to the disease pathogenesis. While the function of these proteins in health and disease are not completely understood, recent studies are providing insight into underlying disease mechanisms, a critical step toward the development of gene-based therapies. In this review, genes known to cause early-onset glaucoma or contribute to adult-onset glaucoma are organized according to the cell processes or biological systems that are impacted by the function of the disease-related protein product.

Keywords: Autophagy; Caveolins; Complex trait; Extracellular matrix; Glaucoma; Inheritance; Lipid metabolism; Mendelian trait; NOS3; Ocular development; Regulation of cell cycle; TGF-beta; TNF-alpha.

Figure 1

Frequency and effect size of gene variants in glaucoma. Mutations in genes causing early-onset Mendelian forms of glaucoma are rare but have large biological effects (MYOC, OPTN, TBK1, FOXC1, PITX2, PAX6, CYP1B1, LTBP1). Variants in genes influencing the susceptibility to adult-onset forms of glaucoma with complex inheritance are generally relatively common and individually have small biological effects (CDKN2BAS, TMCO1, SIX6, CAV1/CAV2, ABCA1, AFAP1, FNDC3B, GAS7, PLEKHA7, GMDS, PMM2, TGFBR3, COL11A1, 8q22). COL15A1 and COL18A1, modifiers of early-onset glaucoma, have intermediate frequency and effect size (not shown in this figure). Variants in LOXL1 contributing to exfoliation syndrome are common but also have large biological effects.

Figure 2

CDKN2BAS and cell cycle progression. CDKN2BAS (Cyclin dependent kinase inhibitor 2B antisense) is a long noncoding antisense RNA that regulates expression of CDKN2B (cyclin dependent kinase inhibitor 2B), coding for an inhibitor of CDK4 (cyclin-dependent kinase 4) necessary for cell cycle progression.^–