{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMYOC encodes myocilin, a secreted glycoprotein highly expressed in ocular tissues such as the trabecular meshwork and ciliary body. In its wild‐type form, myocilin exhibits an olfactomedin-like domain that mediates specific protein–protein interactions, is processed by intracellular proteases (including calpain) and traffics via unconventional secretory pathways (for example, associated with exosome‐like vesicles) rather than classical secretion. In addition, myocilin can modulate cell adhesion and extracellular matrix signaling (notably through interactions with components such as fibronectin and the heparin II domain) and is regulated by factors including glucocorticoids. These normal functions are reflected in studies that have characterized its genomic variations and promoter polymorphisms associated with intraocular pressure control and primary open-angle glaucoma (POAG)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA significant body of work has shown that disease-causing MYOC mutations disrupt its normal proteolytic processing and secretion. Mutated myocilin frequently accumulates within the endoplasmic reticulum—leading to intracellular aggregation, formation of amyloid-like fibrils, and endoplasmic reticulum stress—and can alter downstream signaling pathways. In several studies, the impairment of endoproteolytic cleavage (and consequent misfolding) has been linked to toxic gain-of-function effects that compromise trabecular meshwork cell viability. In addition, MYOC mutations have been implicated in digenic or modifying interactions with other glaucoma-related genes such as CYP1B1 and OPTN, thereby influencing disease onset and severity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its intrinsic cellular functions, myocilin appears to interact with multiple glaucoma-associated pathways and gene products that modulate the disease phenotype. Experimental models using transgenic mice, as well as investigations into the effects of mutant myocilin on Wnt signaling and Rho-mediated cytoskeletal dynamics, have underscored its role in altering aqueous humor outflow and intraocular pressure. Furthermore, interactions with genes such as CYP1B1, OPTN, and even novel candidates like noelin/optimedin reveal a complex regulatory network that may determine glaucoma onset, penetrance, and progression. Recent structural insights into the olfactomedin domain of myocilin have provided further clues regarding its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "50"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J H Fingert, A F Clark, J E Craig, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Association of a single nucleotide polymorphism in the TIGR/MYOCILIN gene promoter with the severity of primary open-angle glaucoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1034/j.1399-0004.2001.600308.x"}], "href": "https://doi.org/10.1034/j.1399-0004.2001.600308.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11595024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11595024"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Andrea L Vincent, Gail Billingsley, Yvonne Buys, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/340733"}], "href": "https://doi.org/10.1086/340733"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11992263"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11992263"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mario Torrado, Ritu Trivedi, Rina Zinovieva, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2004.020024"}], "href": "https://doi.org/10.1136/jmg.2004.020024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15342693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15342693"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Donna M Peters, Kathleen Herbert, Brenda Biddick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Myocilin binding to Hep II domain of fibronectin inhibits cell spreading and incorporation of paxillin into focal adhesions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2004.09.026"}], "href": "https://doi.org/10.1016/j.yexcr.2004.09.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15652337"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15652337"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Subhabrata Chakrabarti, Kiranpreet Kaur, Sreelatha Komatireddy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gln48His is the prevalent myocilin mutation in primary open angle and primary congenital glaucoma phenotypes in India."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2005)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15723004"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15723004"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "K Kaur, A B M Reddy, A Mukhopadhyay, et al. 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