**2. Genetic basis of glaucoma**

Glaucomas are genetically heterogeneous. Very few cases of glaucoma exhibit typical Men‐ delian inheritance, though familial history increases the risk factor [11, 12]. Majority of glau‐ coma cases appear to be multifactorial that are affected by multiple genetic and (or) environmental factors. In certain cases, mutations in some genes may cause glaucoma only when present in a susceptible genetic background. These and other complexities confound genotype-phenotype associations, making it difficult to identify genes that actually cause the disease. As a result, only a small fraction of glaucomas are associated with mutations in specific genes. Genetic studies have led to the identification of over 20 chromosomal loci that have been linked to glaucoma: GLC1A-1N, GLC3A-3C [5]. However, only five genes have so far been linked to glaucoma. While four genes – *Myocilin/TIGR* (trabecular mesh‐ work inducible glucocorticoid response), *Optineurin*, *NTF4* (neurotrophin 4) and *WDR36* (WD repeat 36), have been shown to be associated with POAGs, *CYP1B1* (cytochrome p450-1B1) has been linked to congenital glaucoma [5, 6, 11, 13, 14]. But mutations in CYP1B1 have been shown to be associated with POAG also [15, 16]. A better understanding of the genetic basis of the disease, with the genes involved, is critical for early detection of the dis‐ ease and development of therapeutic agents that can target specific pathways.

**Figure 1. Disease associated mutations in optineurin.** Schematic of optineurin, showing its various domains. CCcoiled coil, UBD- ubiquitin binding domain, LZ- leucine zipper, LIR- LC3 interacting region, ZF- zinc finger. A. Various glaucoma causing mutations identified in the optineurin. Of these, R545Q and M98K are polymorphisms. B. Amyotro‐ phic Lateral Sclerosis (ALS) associated mutations in optineurin. Deletion of some of the exons have been found in ALS patients but not in glaucoma patients. C. Schematic shows regions of optineurin interacting with various proteins. Htt-Huntingtin, a protein found to be mutated in Huntington's disease; mGluR- metabotropic glutamate receptor; MYPT1- myosin phosphatase targeting subunit 1; TBK1- TANK binding kinase 1; RIP1- receptor interacting protein 1.

Functional Defects Caused by Glaucoma – Associated Mutations in Optineurin

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Rezaie et al. (2002) showed that certain mutations in the coding region of the gene *OPTN* are associated with 16.7% of the families with NTG, the only gene to be implicated in this sub-type of POAG. One of the mutations, in which glutamic acid at 50th position is replaced by lysine (E50K), segregates with the disease in a large family affected with NTG [18]. This provided strong evidence for the conclusion that this mutation in optineurin causes glaucoma. Such strong evidence is not available for other mutations of optineurin but some of the mutations

**3. Glaucoma-associated mutations in optineurin**

Mutations in the gene *OPTN*, which encodes the protein optineurin (optic neuropathy in‐ ducing), cause NTG and amyotrophic lateral sclerosis (ALS) [17, 18]. Both of these are neu‐ rodegenerative diseases. Like glaucoma, ALS is also a progressive disease, which involves degeneration of motor neurons in the primary cortex, brainstem and spinal cord [19]. Opti‐ neurin is also seen in pathological structures present in some other neurodegenerative dis‐ eases, such as Alzheimer's disease and Parkinson's disease [20]. Despite its association with glaucoma almost a decade ago, the cellular functions of optineurin, and how its mutations alter these functions, are beginning to be understood only now. This review focuses on the recent advances in cellular functions of optineurin and defective molecular events because of optineurin mutations.

**Figure 1. Disease associated mutations in optineurin.** Schematic of optineurin, showing its various domains. CCcoiled coil, UBD- ubiquitin binding domain, LZ- leucine zipper, LIR- LC3 interacting region, ZF- zinc finger. A. Various glaucoma causing mutations identified in the optineurin. Of these, R545Q and M98K are polymorphisms. B. Amyotro‐ phic Lateral Sclerosis (ALS) associated mutations in optineurin. Deletion of some of the exons have been found in ALS patients but not in glaucoma patients. C. Schematic shows regions of optineurin interacting with various proteins. Htt-Huntingtin, a protein found to be mutated in Huntington's disease; mGluR- metabotropic glutamate receptor; MYPT1- myosin phosphatase targeting subunit 1; TBK1- TANK binding kinase 1; RIP1- receptor interacting protein 1.
