Disease relevance of MYOC

• MYOC mutations included cases of juvenile glaucoma with or without pigmentary glaucoma and mixed-mechanism glaucoma [1].
• Instead, two polymorphisms in the TIGR gene and three polymorphisms in the OPTN gene, in which one was novel, were found in three phenotypes: POAG, exfoliative glaucoma, and exfoliation syndrome [2].
• POAG caused by DCV at MYOC has been termed "myocilin glaucoma". Clinically, DCV at MYOC may manifest as a typical POAG, normal tension glaucoma, or ocular hypertension without glaucoma [3].
• METHODS: Myocilin full length (1-504 amino acids) and two truncated proteins, myocilin 1-270 and 271-504, were expressed and purified from an E. coli strain, Rosetta2(DE3)pLysS [4].
• The eukaryotic myocilin was purified from cultured medium of a transformed TM cell line (TM5) transduced with feline immunodeficiency virus that contains an internal cassette expressing full length myocilin [4].

Psychiatry related information on MYOC

• RESULTS: Univariate analysis showed that POAG was related to family history, cardiovascular disease, alcohol consumption and a myocilin sequence alteration (T353I) (P < 0.04) [5].

High impact information on MYOC

• Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A) [6].
• Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma [7].
• A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping [8].
• PE/TIGR provokes genome sequencing skeptics [9].
• We also propose that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway [1].

Chemical compound and disease context of MYOC

• The interactions with the Hep II domain of fibronectin could alter cell-matrix interactions in the TM and provides an interesting lead to explore the role(s) of TIGR/MYOC in both steroid-induced and primary open angle glaucoma [10].
• MYOC encoding a 55kDa secretory glycoprotein named myocilin is closely linked to primary open-angle glaucoma (POAG) [11].
• METHODS: A feline immunodeficiency virus vector encoding both full-length myocilin (amino acids 1-503 fused to C-terminal V5 and six-histidine epitopes) and puromycin resistance was used to transduce a transformed trabecular meshwork cell line (TM5) [12].
• PURPOSE: To identify a rapid and reliable method to detect the Glutamine 368 STOP (Q368STOP) disease-predisposing allele of the myocilin gene associated with adult onset, primary, open-angle glaucoma [13].

Biological context of MYOC

• In addition, APOE(-491T), interacting at a highly significant level with an SNP in the MYOC promoter, MYOC(-1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG [14].
• This work emphasizes the genetic heterogeneity of juvenile glaucoma and suggests, for the first time, that (1) congenital glaucoma and juvenile glaucoma are allelic variants and (2) the spectrum of expression of MYOC and CYP1B1 mutations is greater than expected [1].
• Individuals carrying both the MYOC T377M variant and the GLC1C haplotype were more severely affected at an earlier age than individuals with just one of the POAG genes, suggesting that these two genes interact or that both contribute to the POAG phenotype in a cumulative way [15].
• The goal of this study was to determine whether mutations in the myocilin (MYOC) gene on chromosome 1 are present in two POAG families, which have previously been mapped to the GLC1C locus on chromosome 3 [15].
• METHODS: The three exons of MYOC were screened by denaturing (d)HPLC [15].

Anatomical context of MYOC

• The COS-7 cell line was transfected with expression vectors encoding wild-type or mutated MYOC complementary DNA [16].
• The purpose of the present study was to better understand the mechanism of extracellular transport of MYOC in trabecular meshwork cells [17].
• The association of MYOC with exosome-like membranes appeared to be specific, on the extracellular face, and reversible [17].
• Taken together, data suggest that MYOC appears in the extracellular space of trabecular meshwork cells by an unconventional mechanism, likely associated with exosome-like vesicles [17].
• When intracellular membranes were separated over a linear sucrose gradient, MYOC equilibrated in a fraction less dense than traditional secretory vesicles and lysosomes [17].

Associations of MYOC with chemical compounds

• In pulse-labeling experiments that followed nascent MYOC over time, the characteristic doublet observed for MYOC by SDS-PAGE did not change, even in the presence of brefeldin A; indicating that MYOC is not glycosylated and is not released via a traditional secretory mechanism [17].
• Overexpression of GRbeta in glaucomatous TM cells inhibited DEX induction of a luciferase reporter gene as well as the endogenous genes MYOC and fibronectin [18].
• Myocilin therefore appears to specifically block functions mediated by the Heparin II domain possibly through direct interactions with it [19].
• The effect of myocilin on focal adhesions could be overcome by treating cells with either phorbol 12-myristate (PMA) or oleoyl-L-alpha-lysophosphatidic acid (LPA) [19].
• Colloidal gold labeling was also performed using an anti-human myocilin polyclonal antibody [20].
• These results demonstrate that myocilin has a de-adhesive activity and triggers signaling events. cAMP/PKA activation and the downstream Rho inhibition are possible mechanisms by which myocilin in overabundance may lead to TM cell or tissue damage [21].

Physical interactions of MYOC

• In solid phase binding assays, 125I-TIGR/MYOC bound fibronectin but not laminin or type IV collagen [10].
• Identification of flotillin-1 as a protein interacting with myocilin: implications for the pathogenesis of primary open-angle glaucoma [22].

Other interactions of MYOC

• Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene [14].
• We studied the role of MYOC, CYP1B1, and PITX2 in a population (n=60) affected with juvenile or early-onset glaucoma from the greater Toronto area [1].
• Two single-nucleotide polymorphisms (SNPs) in OPTN (c.412G-->A and c.603T-->A) and one SNP in MYOC (c.227G-->A) were examined [23].
• RESULTS: MYOC, OPTN, and WDR36 mutations were excluded in all family members [24].
• No disease causative mutations have been identified in MYOC or ABCA4 [25].

Analytical, diagnostic and therapeutic context of MYOC

• Cellular and secreted MYOC proteins were characterized by Western blotting [16].
• METHODS: All coding exons of the OPTN and MYOC genes were amplified by PCR from genomic DNA and subjected to direct DNA sequencing [26].
• PURPOSE: To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC) [27].
• Mutation and sequence analyses showed a novel missense mutation, c.821C > G (p.P274R), in the C-terminal olfactomedin domain coded by exon 3 of the MYOC gene [28].
• Genetic dissection of myocilin glaucoma [3].

References