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

Angle closure glaucomas (ACGs) are relatively rare among Caucasians and usually are acute. It is the most common form of glaucoma in Asian population [8, 9]. In ACGs, the iri‐ diocorneal angle is closed, blocking the drainage of aqueous humor and resulting in eleva‐ tion of IOP. People with shallower anterior chamber, with hypermetropia and hence narrower angles, are more susceptible to ACGs. Unlike POAG, ACG can be associated with symptoms like eye pain, blurred vision, headache, nausea, and hence is usually detected

In developmental or congenital glaucoma, developmental anomalies in tissues like trabecu‐

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.

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

lar meshwork and Schlemm's canal cause optic neuropathies [5].

earlier [10].

104 Glaucoma - Basic and Clinical Aspects

**2. Genetic basis of glaucoma**

of optineurin mutations.

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 have not been found in normal population. The E50K mutation was found in 13.5% of affected families [18]. Subsequent studies have identified several other mutations in optineurin that are associated with adult onset NTG and in rare cases of juvenile onset glaucoma. However, the frequency of optineurin mutation in sporadic cases is low, generally less than 1%. A polymor‐ phism in optineurin, M98K, is associated with glaucoma in some South Asian populations but not in Caucasians [21, 22]. Most of these optineurin mutations are missense mutations (mutation which leads to replacement of the pre-existing amino acid with another). One of the rare mutations is an insertion in exon5, which would lead to production of a truncated protein due to frameshift [18] (Figure 1A). Certain point mutations that do not cause a change in amino acid sequence, for example, V148V, have also been reported [23]. Recently, certain mutations in optineurin have been shown to cause ALS [17, 24-26]. These mutations are mostly different from those that cause glaucoma (Figure. 1B). Almost all the glaucoma-associated mutations of optineurin are single copy alterations, indicating therefore, that these are likely to be dominant. An alternate possibility is that these point mutations cause a loss of function and the resulting haploinsufficiency may cause the disease.

selection of cargo and budding of a vesiculo-tubular transport intermediate, movement of this vesicle on a cytoskeletal track, tethering or docking with an appropriate target compartment and finally fusion of the vesicle with the target membrane [50]. Several proteins like small GTPases, motor proteins, SNAREs (Soluble *N*-ethylmaleimide sensitive-factor-Attachment Protein Receptors), tethers, etc. mediate different steps of vesicular trafficking. One family of proteins, which mediates virtually all these steps in vesicular trafficking, is a class of Ras superfamily of small GTPases, the Rab GTPases (Ras-like GTPases in brain) [51, 52]. Rab GTPases confer identity to certain vesicular intermediates and organelles inside the cell, e.g. Rab5 associates with early endosome or sorting endosome and acts as a marker for it. Apart from imparting vesicle identity to some organelles, these Rab GTPases act as master regulators of trafficking events controlling vesicle budding, vesicle fusion, signal transduction and motility [53]. Rab GTPases function as molecular switches in the cell as they exist in two different forms, a GTP-bound active form that is membrane associated, and a GDP-bound

Functional Defects Caused by Glaucoma – Associated Mutations in Optineurin

http://dx.doi.org/10.5772/52692

107

**Figure 2. Functions of optineurin.** Optineurin is involved in several cellular pathways. Schematic shows various func‐ tions performed by optineurin inside the cell. Proteins shown in the boxes are the ones involved in these pathways.

Most of these proteins are involved in direct interaction with optineurin.

inactive form that is cytoplasmic.
