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   Table of Contents      
Year : 2004  |  Volume : 52  |  Issue : 4  |  Page : 271-80

A review of genetic and structural understanding of the role of myocilin in primary open angle glaucoma.

Department of Genetics, Aravind Eye Hospital, Madurai

Correspondence Address:
J Kanagavalli
Department of Genetics, Aravind Eye Hospital, Madurai

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Source of Support: None, Conflict of Interest: None

PMID: 15693317

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Primary open angle glaucoma (POAG) is the most common form of glaucoma and the second leading cause of blindness in the world. Discovery of the candidate gene MYOC (TIGR/MYOC) encoding the protein myocilin, believed to have a role in cytoskeletal function, might play a key role in understanding the pathogenesis of POAG. MYOC is expressed in many ocular tissues, including trabecular meshwork (TM), a specialised eye tissue essential in regulating intraocular pressure (IOP). Later it was shown to be the trabecular meshwork inducible-glucocorticoid response protein (TIGR). Mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma (JOAG). The unprocessed myocilin with signal peptide is a 55-kDa protein with 504 amino acids. Mature myocilin is known to form multimers. Wild type myocilin protein is normally secreted into the trabecular extracellular matrix (ECM) and there appears to interact with various ECM materials. It is believed that the deposition of high amounts of myocilin in trabecular ECM could affect aqueous outflow either by physical barrier and/or through cell-mediated process leading to elevation of IOP. The N-terminal region of the myocilin has sequence similarity to myosin (muscle protein) and the C-terminal of the protein has an olfactomedin-like domain. Structural and genetic studies of the MYOC gene and its protein product along with molecular modeling could lead to better understanding of the pathogenesis of POAG. This review highlights the current understanding of myocilin and the relevance of genetic and structural work.

Keywords: Primary open angle glaucoma, myocilin, GLC1A, TIGR/MYOC

How to cite this article:
Kanagavalli J, Pandaranayaka E, Krishnadas SR, Krishnaswamy S, Sundaresan P. A review of genetic and structural understanding of the role of myocilin in primary open angle glaucoma. Indian J Ophthalmol 2004;52:271

How to cite this URL:
Kanagavalli J, Pandaranayaka E, Krishnadas SR, Krishnaswamy S, Sundaresan P. A review of genetic and structural understanding of the role of myocilin in primary open angle glaucoma. Indian J Ophthalmol [serial online] 2004 [cited 2020 Jun 3];52:271. Available from: http://www.ijo.in/text.asp?2004/52/4/271/14570

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Glaucoma is a term used to describe a group of disorders that have in common a characteristic degeneration of the optic nerve associated with typical visual field defects and usually elevated intraocular pressure (IOP).[1] If left untreated, It results in absolute irreversible blindness. Glaucoma is a leading cause of irreversible blindness throughout the world It is estimated that 66.8 million people worldwide have glaucoma and that 6.7 million are bilaterally blind.[2] In India Year 2000 statistics, glaucoma accounts for 1.52% of the blindness (8.1 million blind persons).[3]

Primary open angle glaucoma (POAG) is the most common autosomal dominant disease, representing approximately half of all cases of glaucoma.[4] Despite many decades of research, little is known about the precise molecular defects and abnormal biochemical pathways that result in glaucoma. The obstruction to the aqueous humor outflow pathway through the trabecular meshwork is the major cause of increase in IOP in POAG. Several research groups used linkage analysis to study Juvenile open angle glaucoma (JOAG) pedigrees, a subset of POAG. They have narrowed the search to a region on chromosome 1.[5] This linkage site was designated as GLC1A where one of the genes, myocilin ( MYOC ), within the GLC1A locus was first identified by cell biology experiments. It has been reported that mutations in the MYOC gene cause both adult-onset and juvenile-onset open angle glaucoma.[6] This means that the product of this gene might be related in some way to the IOP elevation in POAG. MYOC, which encodes a 55 kDa protein myocilin (Swissprot Acc: Q99972) and was previously termed trabecular meshwork inducible-glucocorticoid response protein (TIGR), was identified as an up-regulated molecule secreted by cultured human trabecular meshwork cells after the treatment with glucocorticoids such as dexamethasone.[7],[8] The normal physiologic function of myocilin in the cell is not known. It might serve a structural function within the cytoplasm, or it might be associated with other molecules in the cell, perhaps as a molecular chaperone. Extracellularly it might be involved in creating resistance to aqueous outflow by binding to other extracellular molecules or to the cell membrane of trabecular cells. A correlation has been found between specific mutations in the MYOC gene and the clinical course of glaucoma. Not all cases of POAG have a mutation in the MYOC gene. This suggests the association of other yet unidentified, proteins or factors. One other possibility supported by the structural model of myocilin[9] is that the induced conformational changes in the protein could cause the disruption of the dimer or oligomer formation (see later), leading to protein aggregation and occurrence of glaucoma.

  Risk factors for the development of POAG Top

A variety of risk factors are associated with the development of POAG. The risk of developing POAG can be correlated with an elevation in IOP.[1] Other risk factors include use of anti-inflammatory cortico-steroids,[10],[11] race (African-Americans have a 4-fold increased risk of developing POAG[4] and family history (first degree relative with glaucoma.)[12] Nevertheless many cases of glaucoma do not correlate with these risk factors. It has been proposed that some of these involve glutamate-mediated exotoxicity on Muller cell protection of retinal ganglion cells.[13] It has been suggested that functional disorders of glutamate uptake in retinal Muller glial cells might be one of the aetiologies of glaucoma.

  Genetics of POAG Top

The discovery of MYOC as one of the candidate genes for open angle glaucoma has provided new opportunities for research on glaucoma. The association of MYOC with glaucoma provides a key to understanding the physiology of aqueous outflow through the TM, and the pathophysiology of POAG.[14],[15],[16] Mutations in the MYOC gene on human chromosome 1 have been linked to POAG.[6]

A common nomenclature and classification system for glaucoma genetics have been introduced.[17], [18] The Human Genome Organization (HUGO) genome database nomenclature committee approved the gene symbol GLC1 for POAG, and denoted letters A, B, C and so on for each new locus that would be identified. The chromosomal locations of six genes that can independently cause POAG have been mapped [Table - 1]. In addition, a new locus GLC1G in chromosome 2p21 corresponding to the gene CYP1B1 for chronic adult-onset primary open angle glaucoma has been claimed (www. dsi.univparis5.fr/ genatlas / phenotype.php? symbol = GLC1G) but not yet published. The CYP1B1 gene has already been mapped to the GLC3A locus for primary congenital glaucoma.[19]

  Identification of MYOC as a candidate gene for glaucoma Top

Three major approaches are used to search for disease-causing genes: (1) candidate gene approach, (2) utilising clues from chromosomal deletions and translocations, and (3) linkage analysis. A combination of all the three strategies is also used.

The candidate gene approach is useful when there is a known gene whose function makes it a strong suspect. Unfortunately there are too many potential candidate genes for POAG, including all the genes involved in the development, structure and function of the trabecular meshwork and optic nerve head. By utilising the clues from the chromosomal deletions and translocations the second approach identifies the patients who manifest the disease of interest.

In the absence of any other clue as to the location and nature of the gene causing the disease, linkage analysis is performed on large families affected with disease. In linkage analysis we look for co-segregation between a disease phenotype and polymorphic genetic markers. When recombination occurs, a given allele of a marker is more likely to remain physically connected to the disease-causing gene if the marker and the gene are in close proximity. The goal in linkage analysis is to find a marker that is so close to a disease-causing gene that the marker and the gene remain together during meiosis more frequently than can be explained by chance. More than 50 inherited disorders have glaucoma as a feature.[20] The defect in genes causing any one of these 50 disorders would have to be considered as a potential candidate. Although a direct evaluation of all of the potential candidate genes is impractical, one can use genetic linkage analysis to help choose among the list for mutation screening. Once the area of interest is narrowed to a small portion of one chromosome, then any genes in the area that are expressed in the eye become important candidate genes. This combination of positional information and candidate gene screening has been termed the positional cloning approach. Using a positional cloning approach, potential disease-causing genes are identified and evaluated based on their chromosomal location and fine mapping chromosomal rearrangements in rare patients with grossly abnormal karyotypes.

Several research groups used linkage analysis to study JOAG pedigrees in search of a JOAG disease-causing gene in the hope that the same gene might also be involved in the pathogenesis of POAG. In 1993, Sheffield et al mapped the location of a gene that causes JOAG to a region on chromosome 1 (1q21-31) using linkage analysis [Figure - 1].[5] This locus was designated as GLC1A ("GLC" stands for glaucoma, "1" designates primary open angle and "A" stands for the first linkage for this disease). A number of other groups subsequently identified additional families in which JOAG mapped to the locus.[21],[22],[23] Recombination observed between the glaucoma phenotype and highly polymorphic genetic markers in two large JOAG kindreds narrowed the interval containing GLAC1A gene to 3-centimorgan region of chromosome 1q between markers D1S3665 and D1S3664.[24] Subsequent linkage studies of additional JOAG families confirmed that a JOAG gene was located in chromosome 1.

By yeast artificial chromosome (YAC) sequenced tagged site (STS) content and radiation hybrid mapping, three genes namely APT1LG1 , TXGP1 and TIGR were found to map within the narrowest GLC1A interval.[25] Polansky et al hypothesized that steroid-induced ocular hypertension (OHT) and possibly POAG might be mediated through glucocorticoid induction of specific genes in the trabecular meshwork.[8] Changes in the gene expression of trabecular meshwork cells were determined by comparing corticosteroid treated cells with control cells and a protein was discovered that markedly increased when the trabecular meshwork cells were exposed to corticosteroids. The protein was named trabecular meshwork-inducible glucocorticoid response protein ( TIGR ). In 1997, Stone et al cloned the cDNA encoding TIGR protein and subsequently mapped it to within the chromosome1q GLC1A locus.[6] The TIGR gene was screened in JOAG and POAG pedigrees for disease-causing mutations by a combination of single strand conformation polymorphism analysis (SSCP) and direct sequencing. These techniques were performed to determine any alterations in the gene that might change an amino acid in the resultant protein. If such a variation is identified it is suspected to be a disease-causing mutation, when the sequence variation is seen much more commonly in patients than in unaffected individuals.[69]

Japanese researchers reported the discovery of a protein associated with cytoskeleton in the retina and termed it myocilin because it shared the homologous regions with myosin.[26] Myocilin was the same protein that was named TIGR by Polansky et al.[8] In 1998, HUGO assigned the gene the name myocilin and it is now referred to as MYOC and not TIGR .

  Cellular role of myocilin Top

There is evidence for a potential intracellular role of myocilin.[26],[27],[28] Based on a study of the distribution of myocilin green fluorescent protein (GFP) fusion protein in transfected cells,[29] it has been reported that myocilin might have an intracellular role This study reported that myocilin GFP is localised in cytoplasmic vesicles associated with microtubules. The intracellular role of myocilin was suggested at the Glaucoma Research Foundation meeting based on the observed cellular localisation of myocilin GFP fusion proteins.[28],[30],[31] It is suggested that myocilin is a member of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family of vesicle trafficking and targeting proteins and serves as a molecular address on secretory vesicles destined for nascent junctions.[28] Immunohistochemical study indicates that myocilin protein is found in TM cells, trabecular beams, and the connective tissue of the juxtacanalicular part of the human TM in situ.[32] In addition, cell fractionation experiments and western blotting indicate that the 55 kDa and 66 kDa forms of myocilin are associated with the mitochondrial fraction of trabecular meshwork.[33]

MYOC mutations in POAG

The myocilin gene consists of three exons, which encodes for 55 to 57 kDa myocilin protein with 504 amino acids and an isoelectric point of approximately 5.21.[26],[34],[35] Mutations in MYOC gene were reported initially in 1997.[6] The majority of mutations occur in the third exon of the MYOC gene, which encodes the olfactomedin-like domain [Figure - 2]. Research groups around the world have identified more than 50 missense or nonsense variants in MYOC . In addition to glaucoma-causing MYOC mutations, numerous sequence changes in MYOC have also been discovered. They are not associated with the disease and only represent polymorphisms. [36],[37],[38] In the absence of functional assay, sequence changes that alter the size, electrical charge or polarity of the encoded myocilin have been considered more likely to cause disease than variations that do not cause such changes.[36] Some mutations have been found to have a significantly higher prevalence among glaucoma patients than among the control populations, such as the Gln368Stop mutation.[37] Several MYOC mutations have been shown to segregate with glaucoma in a statistically significant manner. These include Tyr437His, Ile477Asn, Gln368Stop, Thr377Met, 396INS397 and Gly364Val.[37] In our study of the Indian POAG population, Thr377Met and Gly367Arg were reported as disease-causing mutations.[9] Other studies carried out in the Indian POAG population showed a putative novel mutation Gln48His in exon 1[39],[40] and Pro370Leu in exon 3 of MYOC .[39] The probable disease-causing and non disease-causing mutations of MYOC have been cited in the Human Genome Mutation Database (http://www.mutdb.org/AnnoSNP/data/M3/S0/R2/AC.nt.html). The prevalence of MYOC mutations has been assessed in many different populations of POAG patients. In each group studied, approximately 3% of POAG patients harbored MYOC mutations. In Indian POAG patients the frequency of MYOC mutations is only about 2%.[9],[40] The locations of the predicted protein modification sites and mutations in myocilin protein have been described for 33 published MYOC mutations.[41] Predicted and assayed protein alterations for 13 MYOC non-synonymous sequence variants [Table - 2] have been described. One common mutation, Gln368STOP, occurs in adult-onset POAG patients and results in a 135 amino acids truncated myocilin protein (approximately half of the Olfactomedin domain). The IOP in this case may be normal or moderately raised and it is usually controlled with medication. [42],[43],[44] Some of the known mutations[37] and the two mutations identified by our study were analysed using our structural model.[9] They are all surface exposed. There are no mutations in the mid-region. Both the mutations, Gly367Arg and Thr377Met identified in our study, map on to the C-terminal region.

  Role of MYOC mutations in pathogenesis of POAG Top

There are two pathways to drain the aqueous humor to maintain the IOP. The majority of outflow in the healthy human eye occurs at the anterior chamber angle formed by the insertion of the iris root and the peripheral cornea[45] [Figure - 3]. Here aqueous humor flows through the trabecular meshwork and enters Schlemm's canal, where it joins the general venous drainage of the eye. The second outflow occurs through the uveoscleral route, which appears to be a relatively minor pathway in the normal human eye. It is important to regulate the aqueous humor outflow through the trabecular meshwork for the maintenance of an appropriate IOP.[46] In the case of glaucoma, the IOP is raised due to a defect in the regulation of this outflow. Myocilin is normally present in a variety of ocular tissues including trabecular meshwork, cornea, retina, optic nerve, ciliary nerves, and in non-ocular tissues like heart, skeletal muscle, stomach, thyroid, bone marrow, prostate, intestine, lung, pancreas and lymph node.[47],[48] In addition to trabecular meshwork, several other ocular tissues release myocilin into the aqueous humor.

Myocilin, when present in excessive amounts in the trabecular meshwork either due to overproduction or decreased degradation, could cause increased resistance to aqueous humor outflow by binding to aqueous outflow pathways. If synthesis of a mutant myocilin protein escapes the normal feedback regulation, excess myocilin or its mutant form could increase aqueous resistance. An alternative mechanism of glaucoma may be that the mutant form of myocilin is unable to perform its normal physiologic function of IOP regulation. It has been learnt that the myocilin may be required to maintain IOP in vivo . In the aqueous humor it participates in modulation of the outflow and has a tendency to decrease the aqueous outflow. The mechanism by which the protein increases resistance through the TM has not been elucidated.

Some mutations cause more problems than others. This is supported by findings of clinical correlation between various mutations and the onset and severity of glaucoma. The most common mutation, Gln368Stop is associated with older-onset POAG and a lower level of IOP elevation than the reported missense mutations in POAG.[37] This correlation between genotype and phenotype and delayed onset of POAG suggests that this truncated form of protein still has some physiologic function, while the missense mutant proteins are more problematic and cause glaucoma. This mutation produces a truncated form of myocilin. Proper dimerisation or oligomerisation is suggested by our structural model as necessary for the function of normal myocilin protein; the mutations in the MYOC gene prevent proper interactions of this protein.[9] As a result there would be increased production of monomeric forms of myocilin, which could aggregate leading to increased resistance in the trabecular meshwork. The recombinant mutant myocilin protein synthesised by various eukaryotic cell lines were insoluble in Triton X-100 detergent whereas native myocilin was not.[49] To better understand the role of MYOC in glaucoma pathogenesis, the expression of normal and mutant MYOC in cultured ocular and non-ocular cells has been studied.[50] It has been found that normal myocilin is secreted from the cultured cells but very little to no myocilin is secreted from cells expressing five different mutant forms of MYOC. This study suggests that glaucoma is either due to insufficient levels of secreted myocilin or compromised trabecular meshwork cell function caused by congestion of the trabecular meshwork secretory pathway. Accumulation of mutant myocilin in the endoplasmic reticulum and its cytotoxicity in human trabecular meshwork cells has been studied.[51] This suggests that most mutations such as Gly364Val, Gln368Stop, Lys423Glu, Tyr437His and Ile477Asn in MYOC stop the secretion of myocilin. The mutant myocilins expressed were identified as aggregates in the endoplasmic reticulum. There was upregulation of 78kDa glucose- regulated protein and protein disulfide isomerase due to mutant myocilin in endoplasmic reticulum. The postulated effect of diminished cell proliferation, which results in the dysfunction of trabecular cells, was also identified as a cause of glaucoma. Hence this study supports the statement that gain of function is a critical mechanism for POAG rather than haploinsufficiency in individuals with mutations in MYOC .[52]

Morissette et al reported a large French-Canadian family where glaucoma developed in three heterozygous siblings harboring missense mutations at codon 423 but four homozygous mutant siblings were asymptomatic.[53] This MYOC mutation has been claimed to be the first gene defect that causes an autosomal dominant heterozygote-specific disease phenotype in humans, possibly by metabolic interference.[54] The mutant myocilin may have a different shape (secondary or tertiary protein structure) that prevents its interaction with the normal myocilin. However, if both copies of MYOC are mutant (homozygous), the myocilin protein may interact and glaucoma would not result.[53]

  Sequence and structural analysis of myocilin Top

Obviously myocilin has other functions in the normal condition. In human myocilin protein, the first 33 amino acids form the signal peptide. Aminio acids in the region 111-184 form an alpha helical coiled coil region like the myosin tail fibre containing a leucine zipper motif, which is possibly involved in myocilin-myocilin interactions. Myocilin has an olfactomedin-like domain from 246 to 504 amino acids, which is primarily of beta sheet with a disulphide between Cys245-Cys433.[55] Our proposed structural model also shows predominantly beta conformation [Figure - 4]A and includes the abovementioned disulphide bond.[9] Another group using the bioinformatics approach has shown that this cys 433 is conserved among all the proteins in other organisms, and has been identified as being significant similar to myocilin. This residue is conserved in olfactomedin and olfactomedin-like proteins through evolution.[56] The linker region between 185 to 245 amino acids is flexible. Most mutations found in POAG patients are located in the C-terminal region [Figure - 4]B.

  Myocilin Interactions Top

In vitro and in vivo studies show that there are myocilin-myocilin interactions through the leucine zipper motif which dimerize by forming parallel coiled coil helices that wrap around one another through hydrophobic interactions to form homo or heterodimeric proteins.[57] These leucine zippers play a pivotal role in regulating the protein function. When myocilin is subjected to gel electrophoresis under non-reducing conditions it forms complexes. The intramolecular and intermolecular disulfide bond formation could also be responsible for myocilin complex formation. Myocilin forms complexes of high molecular mass aggregates that appear to be dimers and multimers with a molecular weight of 200 kDa and more, whereas its monomer is observed only after treatment with sodium dodecyl sulphate (SDS) under reducing conditions. It is likely that the cysteine residue at position 433 in the olfactomedin domain contributes to this high molecular mass aggregation, because oligomerisation mediated by cysteine residue is a characteristic of olfactomedins. Several other findings suggest that myocilin may exist as a dimer in human aqueous humor. Studies in bovine and monkey aqueous humor suggest that myocilin is present as a dimer and possibly as tetramer or oligomeric structures.[58] Gel filtration studies also showed that myocilin might form homo and hetero dimers. The interaction of myocilin with an olfactomedin-related protein named optimedin has been demonstrated in the rat system using GST pulldown, co-immunoprecipitation and far western binding techniques.[59] The presence of mutant myocilin interferes with the secretion of optimedin in transfected cells. The olfactomedin-like domain of both the proteins interact with each other while the N-terminal domain of both proteins is involved in the formation of protein homodimers. Based on the occurrence of the olfactomedin domain it has also been suggested that the proteins Noelin 1 and Noelin 2 could be involved in interaction with myocilin.[60] This supports the conclusion based on our structural model[9] that POAG is likely to be a disease caused by protein-protein aggregation by conformational changes as in other protein aggregation diseases. Most known mutations of myocilin are also surface exposed on the C-terminal region. The location of these mutations and the truncation of the C-terminal region by Gln368Stop suggest that a plausible mode of action could be the disruption of dimer or oligomer formation by the C-terminal region. This would then allow for greater chances of nucleation of aggregation by the N-terminal region [Figure - 4]C. Upon initiation of aggregation, the hinge region would allow the coiled coil region to become available for further interaction leading to a domino effect. Conformational changes of the N-terminal and hinge regions induced by the molecular environment in the normal protein would disrupt dimer formation, which could also favor aggregation. If this were to be established then, as in other diseases caused by induced conformational changes, mutations alone need not be responsible for the disease as changes in the molecular environment could be causative factors. The discovery of the MYOC gene and its link with the POAG with the predicted model presents a major advancement in understanding the pathophysiology of glaucoma, despite the many unanswered questions on the precise role played by myocilin. It is possible that better understanding of myocilin, such as the ongoing crystallographic characterisation of myocilin by our group, might lead to a breakthrough in unraveling the mechanisms underlying aqueous outflow resistance and ultimately point to therapeutic intervention in POAG.

  Future opportunities Top

The discovery of MYOC as a candidate gene for POAG and discoveries regarding its localisation and regulation in the trabecular meshwork and other tissues point to exciting possibilities to reveal the basic aspects of outflow physiologies as well as pathogenic mechanisms for obstruction. The localisation of myocilin and its interaction with other proteins in TM cells is still not clear. Structural and molecular biology approaches carried out by our group might offer a way to discover the structure-function relations of myocilin and the role of conformation in the aggregation. These studies can be complemented by gene expression and protein expression studies to understand the developmental pathway of POAG, which is triggered by aggregation of myocilin.

  References Top

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  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]

  [Table - 1], [Table - 2]

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