Glaucoma, a group of ocular diseases, is characterized by apoptotic loss of retinal ganglion cells (RGCs) and optic nerve degeneration. It is the leading cause of irreversible blindness with an estimated global prevalence of 3.54% in the population aged 40–80 years. The number of people affected by glaucoma is estimated to reach 111.8 million in 2040 (Tham et al., 2014). Primary glaucoma is categorized into angle closure and open angle types both of which have characteristic RGC and optic nerve damage; however, the drainage angle of the eye is closed or open, respectively. Predominant subtype is the primary open angle glaucoma (POAG). Clinically, POAG is characterized by cupping of the optic disc, visual field defects and an open state of iridocorneal angle and is often associated with elevated intraocular pressure (IOP). A sub-set of patients with POAG like features except for a normal IOP are categorized as normal tension glaucoma (NTG). A meta-analysis of studies published over 20 years has shown a 2.4% global prevalence of POAG with an estimate that 68.56 million people are affected by glaucoma worldwide (Zhang et al., 2021a). Juvenile open angle glaucoma is an uncommon type of POAG that results from developmental abnormalities of aqueous humor outflow pathways. The pigment dispersion syndrome and pigmentary glaucoma are secondary open angle glaucomas characterized by excessive pigment release and dispersion throughout the anterior chamber causing blockade of aqueous outflow. A number of risk factors are known to be associated with the POAG development and progression; among these, elevated IOP is the most well-recognized. Other associated risk factors include age, ethnicity, decreased central corneal thickness (CCT), high myopia, diabetes, hypertension and a family history (Fan et al., 2004).

The diagnosis, monitoring and treatment of glaucoma remain challenging due to several reasons. Distinguishing the clinical appearance of healthy optic nerve from the optic nerve that is undergoing a gradual degenerative process can be quite challenging, particularly in the early stages of the disease progression. This makes it a complex task to accurately assess the precise stage of the disease. Hence, often when detectable visual field loss occurs, significant number of RGCs are already lost. There are wide inter-individual variations in disease progression and therefore, it is often difficult to distinguish patients with rapid disease progression from those with slower disease progression. This also may delay the timely intervention. Moreover, there is significant variation among individual responses to treatment. Hence, there are diagnostic as well as prognostic challenges arising from disease chronicity, clinical heterogeneity and treatability. New technological advances in digital imaging and other investigative procedures have helped to meet some of these challenges. However, a complex multifactorial pathogenesis involved in the onset and progression of glaucoma demands further investigations into novel therapeutic targets and strategies.

The contribution of genetics to the pathogenesis of glaucoma is now well-recognized. Several studies of single-gene variants, genome-wide association studies (GWAS) and whole-exome sequencing have revealed various mutations that have association with glaucoma. In addition, the risk of developing POAG is 10 times higher among first-degree relatives of POAG patients indicating strong disease heritability (Wolfs et al., 1998). Heritability (h2) refers to the proportion of variability of trait due to genetic factors compared to environmental factors and is expressed from 0 to 1. Pooled h2 from various studies have shown a wide range reaching up to an estimate of 0.81 (Asefa et al., 2019). In fact, familial form of the disease has been found to be associated with mutations such as myocilin (MYOC) (encoding myocilin) (Stone et al., 1997), optineurin (OPTN) (encoding optineurin) (Rezaie et al., 2002), and WD-repeat domain 36 (WDR36) (encoding WD repeat domain 36) (Footz et al., 2009), TBK1 (encoding TANK-binding kinase 1), and ASB10 (encoding ankyrin repeat- and SOCS box-containing 10) (Fingert et al., 2011). Furthermore, GWAS have identified several single-nucleotide polymorphism (SNP) associated with POAG. Such associations indicate a genetic control to disease susceptibility, onset and progression and such genetic leads can be utilized to discover key molecular pathways that can explain the disease pathogenesis and to test the newer therapeutic options interacting with appropriate molecular targets.

Form this viewpoint, investigations utilizing animal models based on genetic manipulations offer an attractive option. Utilizing the similarities between mouse and human eyes and ease of using genetic tools in mouse eyes has made genetic mouse models popular to gain insight into the pathobiology of glaucoma and to discover newer treatment options. In this review we highlight the contribution of genetic models in gaining insight into the key molecular pathways involved in the pathogenesis of glaucoma and discuss the use of these animal models to represent human glaucoma endophenotypes. The literature search was made using Pubmed search engine with key words glaucoma, genetic mutations, rodent models, IOP, RGC apoptosis, optic neuropathy in several combinations. The abstracts and full text of all studies were evaluated, and literature published during the years 1995–2023 is included in this review.