**4. Biology of mutant genes**

**2. Genetic contribution to glaucoma: Classification and pathophysiology**

Glaucoma is a group of complex, genetically and clinically heterogeneous condition and af‐ fects all age groups throughout the world [10]. Approximately 70 million people worldwide are affected and it is one of the leading causes of bilateral blindness in humans [11]. The glaucomas are classified into primary and secondary glaucomas and within these two groups the disorder is divided into primary open-angle (POAG; the trabecular mesh work seems to be open and unobstructed by the iris), primary closed angle (PCAG; partial or com‐ plete anterior chamber angle closure) and primary congenital glaucoma (PCG; which mainly affects children). The disorder is characterized by the progressive degeneration of the retinal ganglion cells (RGCs) and is frequently associated with elevated intraocular pressure (IOP) [12]. A host of genetic and environmental factors contribute to the glaucoma phenotypes. For instance in certain population, older age, history of thyroid diseases, higher IOP and high myopia have been reported to be significant risk factors for POAG [13-16]. Similarly, drinking coffee, antioxidant intake and post menopausal hormone use may influence the de‐ velopment of POAG. These environmental risk factors exert their effects on IOP (by decreas‐ ing or increasing) and/or the rate of retinal ganglion cell apoptosis. In advanced glaucoma, the cone photoreceptors were also affected suggesting that photoreceptors may also be se‐

Epidemiological studies suggest that POAG is the most common type of glaucoma in most populations and is consistently associated with elevated IOP [18-19]. However, patients with POAG can also have IOP within the normal range and they are classified as having normal tension glaucoma (NTG) – most likely an independent entity [20]. In NTG, the optic nerve head is just susceptible to normal IOP. This may be due to the difference in the ultra structure of the optic nerve head or due to micro-level of biochemical agents. It is only a lim‐ ited subset of patients with elevated IOP will develop POAG. This is consistent with the finding that, a significant number of glaucoma patients although respond well to therapies to lower the eye pressure, continue to lose vision [21-22]. Many individuals have IOP eleva‐ tion without optic nerve damage (they are considered as having ocular hypertension) and some individuals develop optic nerve degeneration without elevated IOP [10]. Therefore, it has been proposed that elevation in IOP is neither necessary nor sufficient for the onset of the progression of the disorder or optic nerve damage [10, 23-24]. Recent research suggests that transforming growth factor - beta (TGF - beta) and tumor necrosis factor - alpha (TNF alpha) signaling pathways may contribute to the optic nerve disease in glaucoma [10].

The genetic basis of glaucoma is not fully understood. However, familial aggregation, occur‐ rence of bilateral PCG in monozygotic twins and environmental factors such as advanced age, race, vascular risk factors, diabetes and hypertension suggest a multifactorial contribu‐ tion to the etiology of the disease [12, 25-26]. Although details about the inheritance of the

quentially damaged in the disorder [17].

58 Glaucoma - Basic and Clinical Aspects

**3. Primary open-angle glaucoma (POAG)**

Although the exact role of MYOC and OPTN genes in the pathogenesis of glaucoma is un‐ known, it was suggested that myocilin might be involved in the trabecular meshwork (TM) homeostasis. Interestingly, MYOC mutations Y437H and I477N were shown to sensitize cells to oxidative stress induced apoptosis. Similarly, invitro transfection experiments sug‐ gested that mutations in MYOC might also cause mitochondrial defects that may lead to TM cell death. Additionally, biological and cell biological studies demonstrated that mutant MYOC was misfolded and accumulated in the endoplasmic reticulum (ER). This leads to ER stress and activates the unfolded protein response that may cause cellular toxicity and death. However, MYOC gene overexpression is not a cause or effect of elevated IOP. Simi‐ larly, OPTN may have a role in reducing the susceptibility of RGCs to hydrogen peroxideinduced cell death. Mutations in OPTN gene may also cause oxytosis and apoptosis. For instance, OPTN gene regulates endocytic trafficking of transferin receptor that is important for maintaining homeostasis. The E50K mutation of OPTN was shown to impair with traf‐ ficking and this may have implications for the pathogenesis. The TM is the target tissue in the anterior chamber. The development and progression of glaucoma was reported to cause the oxidative damage to the tissue. These changes can be minimized by the use of anti-oxi‐ dants and IOP lowering substances. Therefore, it is possible to reduce the progression of POAG by preventing the oxidative stress exposure to the TM tissue. The WDR gene on the other hand, encodes a member of the WD (tryptophan and aspartic acid) repeat protein fam‐ ily and the members of this family are involved in a variety of cellular processes such as apoptosis and signal transduction. Mutations in the gene may interfere in its normal func‐ tions. Despite strong genetic influence in POAG pathogenesis, only a small part of the dis‐ ease can be explained in terms of genetic mutations.


mapped. More than 60 different mutations in CYP1B1 (or GLC3A) – a member of the cyto‐ chrome P450 superfamily enzyme-encoding gene - have been reported in several PCG fami‐ lies [33-38]. Mutations in CYP1B1 were associated with wide range of phenotypes and the alterations of this gene could impair the morphogenesis of the outflow angle because it has been suggested that CYP1B1 gene participates in iridocorneal angle development [39]. In short, the current concept of glaucoma pathogenesis (Fig. 1) suggests that it is a group of het‐ erogeneous optic neuropathies caused by genetic, epigenetic and environmental factor [40].

Emerging Concept of Genetic and Epigenetic Contribution to the Manifestation of Glaucoma

http://dx.doi.org/10.5772/52279

61

**Figure 1.** A complex glaucoma pathogenesis may include interplay among several factors such as genetic, epigenetic

Inherited glaucoma also occurs in several breeds of dogs including beagles. Primary glauco‐ ma in beagles is inherited as an autosomal recessive trait and appears when the animals are 9 to 18 months old. The pathogenesis, clinical signs and pharmacological responses of glau‐ coma in beagles have been investigated and reported previously [41-43]. Glaucoma in bea‐ gles however, does not involve mutations in MYOC and CYP1B1 genes [44-45]. Similarly, mutations in MYOC gene are unlikely to play a role in the pathogenesis of PCAG in Shiba Inu dogs [46]. Recently, a candidate gene for the beagle model has been isolated [47] and the mutant protein is suggested to be altering the processing of the extracellular matrix that may affect the aqueous humor outflow thereby contributing to the elevated IOP. However, the mechanism underlying RGCs death is not well understood. Interestingly, it was reported that impaired neurotrophin signaling or compromised trophic support as well as p53 medi‐ ated apoptosis may not be the underlying mechanism of RGCs death in a beagle model of glaucoma [48]. Recently, there has been some success in stem cell therapy in animal models [49]. Transplantation of induced pluripotent stem (iPS) cells restored retinal structure and function in degenerative animals. Therefore, these animal models are very useful in further

understanding of the pathogenesis as well as drug development in glaucoma.

and environmental factors.

**7. Inherited glaucoma in animals**

ANP = Atrial natriuretic peptide; MTHFR = methylenetetrahydrofolate reductase; IL-1beta = interleukin 1-beta; NCK = adapter protein 2; OPA1 = optic atrophy-1; PARL = presenilin associated rhomboid-like; EDNRA = endothelin receptor type A; CDKN1A = cyclin dependent kinase inhibitor 1A; HSPA1A = heat-shock 70 kD protein 1A; TNF = Tumor necrosis factor; NOS-3 = nitric oxide synthetase –3; PON1 = paraoxonase –1; TLR4 = toll-like receptor 4; IGF2 = insulin-like growth factor 2;CDH-1 = E-cadherin; TP53 = tumor protein p53; APOE = apolipoprotein E; NTF-4 = neurotrophin 4; AGTR2 = angiotensin II receptor type 2; GSTM1 = glutathione S-transferase mu 1; Asterisk (\*) = detailed references can be found in ref. # 18.

**Table 1.** A partial list of genes that are reported to be associated with POAG and NTG \*
