**8. Pigmentary dispersion syndrome, pigmentary glaucoma and Axenfeld-Rieger syndrome**

factors and histone modifications but it is not clear how DNA demethylation process is ach‐

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

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

63

The other epigenetic marks are posttranslational modifications such as acetylation, methyla‐ tion and phosphorylation of N-terminal tails of histone proteins. They may also regulate gene activity [66] because they affect the chromatin structure. For instance, acetylation of histone H3 and H4 leads to the formation of euchromatin and deacetylation leads to hetero‐ chromatin (tightly packed) formation (see below). These can also be influenced by environ‐ mental factors such as diet. Similarly, miRNAs regulate (down regulation) the translation of mRNAs by binding to their complementary sequence in the 3'untranslated region [69] and

The eye is a model organ for epigenetic studies because external ocular tissues are exposed to the outside environment and may be sensitive to epigenetic effects. Although the epigenetics is well known in diseases such as cancer [71], and hereditary and environmental determi‐ nants have been long suspected for eye disorders [72], epigenetic studies on eye disorders are slowly progressing [9; 73-74]. For instance, retinal and lens differentiation involves specific changes in DNA methylation, expression of non-coding RNA and nucleolar organization [73]. In addition, cell-specific DNA methylation may play an important role in modulating eye specific genes [64]. Similarly, histone modifications were involved in the pathologic course of retinal ganglion cells [75] and site-specific DNA hypomethylation permits the ex‐ pression of interphotoreceptor retinoid binding protein (IRBP) gene [76]. Overexpression of mutant OPTN (E50K) is also found to induce RGC apoptosis [77-78]. Recently, it was also shown that histone deacetylase 4 (HDAC4) was involved in the survival of retinal neurons by preventing apoptosis of rod photoreceptor and bipolar cells [79-80]. Additionally, histone acetyltransferase p300 was found to promote intrinsic axonal regeneration [81]. Similarly, in an animal model (rat/mice), it has been observed that there was a regional gene expression changes including pro-survival, pro-death and acute stress genes [82-84]. Moreover, miRNAs can act as either oncogenes or tumor suppressor genes and can influence the growth of uveal melanoma [85]. Similarly, smoking and nutritional factors were involved in the etiology of

age-related macular degeneration (AMD) in addition to genetic susceptibility [65].

Another example to illustrate the epigenetic effect is the pseudoexfoliation syndrome (XFS), which is one of the most common subtypes of POAG. It is the major risk factor for secon‐ dary POAG. The condition is characterized by a pathological accumulation of the whitish material in the anterior segment of the eye, predisposing to glaucomatous optic neuropathy [86]. The disorder is frequent among Icelanders, increases with age and rarely identified in people below the age of 50. Mutations in the LOXL1 gene were found to be associated with XFS in the Caucasian Australian population. [87]. However, this does not account for the large difference in disease prevalence between different populations. This raises the possi‐ bility of unidentified genetic, racial and environmental modulators [88]. In support of this is

small RNAs are involved in gene silencing at the transcriptional level [70].

**10. The potential role of epigenetics in glaucoma**

ieved [67-68].

A number of ocular conditions such as pigment dispersion syndrome (PDS), Axenfeld-Rieg‐ er syndrome (ARS) can lead to secondary open-angle glaucoma. PDS affects the young peo‐ ple and is characterized by the presence of TM pigmentation, iris-transillumination defects, Krukenberg spindle and backward bowing of the iris [50]. It is transmitted in a direct linear manner from parent to sibling [51]. Genetic analysis revealed a homozygous mutation (C677T) in methylenetetrahydrofolate reductase gene (MTHFR) in a patient [52] and the higher level of plasma homocysteine was suggested to be associated with pigmentary glau‐ coma. Additionally, a gene responsible for the PDS has been mapped to chromosome 7q35 q36 [53]. Regarding pigmentary glaucoma, the risk of developing it from PDS is about 10% at 5 years. Young myopic men are most likely to develop the disorder [54]. Interestingly, PDS and pigmentary glaucoma are not associated with mutations in lysyl oxidase like-1 (LOXL1) and tyrosinase related protein-1 (TYRP1) genes [55-56]. Another anterior segment disease with the risk of developing congenital glaucoma is called ARS. It is a rare autosomal dominant disorder with genetic heterogeneity and exhibits a range of congenital malforma‐ tions of the anterior segment of the eye. In addition, patients with ARS may present system‐ ic malformations such as mild tooth abnormalities, craniofacial dysmorphism, sensory hearing loss and congenital heart defect. It is caused by mutations in paired-like homeodo‐ main 2 (PITX2) and forkhead box C1 (FOXC1) genes [57-61]. In the United States, it has been estimated that mutations in PITX2 and FOXC1 genes are associated with 25% - 30% cases of ARS [62]. In severely affected patients, digenic inheritance of mutations in PITX2 and FOXC1 has also been reported [63].

### **9. Epigenetics: Three major types of epigenetic modifications**

A vast spectrum of epigenetic changes has been described. The most common epigenetic variations involve DNA methylation, various modifications of histones, microRNA (miR‐ NA) and small non-coding RNA expression. All these factors can modulate the expression of genes that in turn may affect phenotypes and response to drugs. DNA methylation may be tissue specific [64] and disrupts the transcriptional activity of genes by affecting the ac‐ cessibility of transcription factors. A large number of CpG residues are concentrated in a re‐ gion of DNA sequence (CpG island). Methylation of cytosine may reduce or prevent the binding of sequence specific transcription factors. This results in changes in gene expression. The CpG region methylation also regulates the expression of a large number of miRNA. On the other hand, genomic hypomethylation may lead to genome instability. This kind of epi‐ genetic abnormality can be influenced by environmental factors such as tobacco smoking, dioxin and nutrition [65] and can lead to complex disorders. Studies including monozygotic twins also suggest that non-Mendelian and complex diseases (including neurological and psychiatric disorders) are likely to be caused by the combination of genetic and epigenetic factors [66]. DNA methylation and its maintenance may depend upon chromatin-associated factors and histone modifications but it is not clear how DNA demethylation process is ach‐ ieved [67-68].

The other epigenetic marks are posttranslational modifications such as acetylation, methyla‐ tion and phosphorylation of N-terminal tails of histone proteins. They may also regulate gene activity [66] because they affect the chromatin structure. For instance, acetylation of histone H3 and H4 leads to the formation of euchromatin and deacetylation leads to hetero‐ chromatin (tightly packed) formation (see below). These can also be influenced by environ‐ mental factors such as diet. Similarly, miRNAs regulate (down regulation) the translation of mRNAs by binding to their complementary sequence in the 3'untranslated region [69] and small RNAs are involved in gene silencing at the transcriptional level [70].
