MYOC

Official Full Name

myocilin

Organism

Homo sapiens

GeneID

4653

Background

MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma. [provided by RefSeq, Jul 2008]

Synonyms

GPOA; JOAG; TIGR; GLC1A; JOAG1;

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Detailed Information

The MYOC gene consists of three exons and two introns, and the three exons are composed of 604, 126 and 782 base pairs, respectively. The 5 kb promoter region contains a number of response elements involved in gene regulation, including: activator protein-1 (AP-1), NFκB, shear stress responsive element (SSRE), Thyroid hormone elements (TRE) and glucocorticoid binding sites. The above-mentioned important motif sequences in the promoter region of TIGR gene are still in the study of the regulation of TIGR gene expression, and it is speculated that these structures are closely related to the influence of environmental/genetic factors on TIGR genes.

The MYOC gene has a cDNA size of 2 kb and its encoded product belongs to mucin/glycoprotein, which exists in both glycosylated and non-glycosylated forms. MYOC is widely expressed in ocular tissues. In addition to the discovery of the MYOC gene in trabecular cells, the cDNA of this gene is also isolated in the ciliary body. The expression of MYOC has been found in tissues such as corneal epithelium, corneal endothelium, corneal stroma, aqueous humor, iris, sclera, ciliary muscle, lens epithelium, sieve plate, retina, and ocular nerve.

Figure 1. Co-aggregation of Grp94 with mutant/misfolded myocilin (80). Grp94, glucose-regulated protein 94. (Wang, H., et al. 2018)

MYOC and Primary Open-angle Glaucoma (POAG)

Studies have shown that there are more than 180 MYOC gene variants, of which about 40 are disease-causing mutations. Most of the disease-causing mutations are clustered on the third exon, less in the first and second exons, and the promoter, intron 1, and intron 2 are also found to have mutations. The primary open-angle glaucoma (POAG) is produced by spreading or aggregating various variant forms of MYOC protein on the endoplasmic reticulum of trabecular meshwork cells. However, changes in wild-type MYOC gene expression do not induce POAG production. MYOC-null mice have neither identifiable effects nor development of glaucoma phenotype during development, suggesting that the MYOC gene is not required for normal intraocular pressure and intraocular morphology. Inhibition of the glycomodulin Grp94 has been reported to be an effective method for the treatment of glaucoma.

Myoc's Pathogenic Mechanism

MYOC is soluble in Triton to form a dimer, and it can also combine with normal cellular components to form a Triton-insoluble polymer, which is involved in the normal physiological activities of the cells. The heterogeneous MYOC combines with other proteins to form macromolecular insoluble aggregates that can cause tissue lysis or cell death. The production of the variant MYOC gene changes the secondary structure of the protein, causing its function to be affected, ultimately leading to the production of POAG. In addition to the accumulation of abnormal MYOC, which can affect the normal function of trabecular meshwork cells, the variation of MYOC in trabecular meshwork cells can cause toxicity and even induce apoptosis of trabecular meshwork cells, which is one of the causes of elevated intraocular pressure. A small amount of MYOC accumulation over a long period of time will cause disease, suggesting that the MYOC secreted by glaucoma patients gradually increases over time. Excessive variation MYOC accumulates in the trabecular meshwork, which also hinders the outflow of aqueous humor and increases intraocular pressure.

References:

Wang, H. , Li, M. , Zhang, Z. , Xue, H. , Chen, X. , & Ji, Y. . (2018). Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (review). International Journal of Molecular Medicine.
Svidnicki, P. V. , Braghini, C. A. , Costa, V. P. , Schimiti, R. B. , & Mônica Barbosa de Melo. (2018). Occurrence of myoc and cyp1b1 variants in juvenile open angle glaucoma brazilian patients. Ophthalmic Genetics, 39(6), 717-724.
Marques, A. M. , Ananina, G. , Costa, V. P. , Vasconcellos, José Paulo Cabral de, de Melo, Mônica Barbosa, & Toland, A. E. . (2018). Estimating the age of the p.cys433arg variant in the myoc gene in patients with primary open-angle glaucoma. PLoS ONE, 13(11).

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