Disease relevance of Myoc

• We developed a genetic mouse model of open-angle glaucoma by expression of mutated mouse myocilin (Myoc) in transgenic (Tg) mice [1].
• Although no structural changes were observed in lenses of animals expressing normal myocilin, lenses with Tyr437His expression developed nuclear cataracts, completely lost transparency, and eventually ruptured [2].
• CONCLUSIONS: The decreased level of Myoc/Tigr mRNA in the retina after induction of elevated intraocular pressure compared with that in the control retina cannot be explained by ganglion cell death alone [3].
• Altered expression of myocilin in the brain of a mouse model for phenylketonuria (PKU) [4].

High impact information on Myoc

• To directly test if increased levels of MYOC can cause IOP elevation and glaucoma, we generated bacterial artificial chromosome transgenic mice that overexpress Myoc at a level similar to that induced by corticosteroid use [5].
• Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP) [6].
• The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC [6].
• We observed a clear difference in the behavior of the two types of TIGR/myocilin; all confirmed mutant proteins tested were substantially Triton insoluble, while normal protein and controls were completely soluble [7].
• Comparison of the resulting gene index with TIGR, UniGene, DoTS, and ESTGenes databases revealed that it had a greater number of transcripts, a greater average number of exons and introns with proper splicing sites per gene, and longer ORFs [8].

Chemical compound and disease context of Myoc

• Myocilin is a secreted glycoprotein that is mutated in some forms of primary open-angle glaucoma (POAG), and patients with the Tyr437His mutation have severe phenotypes [2].

Biological context of Myoc

• Tyr423His and Ile463Ser mutations were introduced into the mouse Myoc protein by in vitro mutagenesis [9].
• Intracellular localization and secretion of wild-type and mutated mouse Myoc proteins were studied in immunostaining and Western blotting experiments, respectively, after transfection into COS-7 cells [9].
• The Tyr423His point mutation, corresponding to the severe glaucoma-causing Tyr437His mutation in the human MYOC gene, was introduced into bacterial artificial chromosome DNA encoding the full-length mouse Myoc gene and long flanking regions [1].
• Mouse myocilin (Myoc) gene expression in ocular tissues [10].
• The mouse and human MYOC/TIGR genes have the same exon-intron structure and contain 3 exons, although the mouse gene is 6 kb shorter than the human gene (10 kb versus 16 kb) due to differences in the length of introns [11].

Anatomical context of Myoc

• However, while wild-type human and mouse Myoc were preferentially located in both the endoplasmic reticulum and Golgi, mutated human and mouse Myoc were located mainly in the endoplasmic reticulum and were excluded from Golgi [9].
• In a functional sense, Myoc expression in the ependyma and choroid plexus, two regions of the brain involved in cerebrospinal fluid synthesis and resorption, parallels Myoc expression in the ciliary body and trabecular meshwork of the anterior segment of the eye where aqueous humor synthesis and outflow occur [12].
• Myoc transcripts were found in high levels in adult eye, heart, brain, skeletal muscle and testis and to a lesser extent in lung and kidney [12].
• Both wild-type (Wt) and Tg animals expressed Myoc in tissues of the irido-corneal angle and the sclera [1].
• Expression of mutated Myoc induced the accumulation of Myoc in cell cytoplasm and prevented its secretion into the extracellular space [1].

Associations of Myoc with chemical compounds

• Dexamethasone upregulates myocilin expression in RGC-5 cells and HT22 hippocampal neurons [13].
• Basal levels of thymidine incorporation but not glycogen synthesis were consistently higher in TIR than in TIGR expressing cells [14].
• Myocilin is a secreted 55-57kDa glycoprotein that forms dimers and multimers [15].
• In TM cells, the expression of myocilin is induced upon treatment with dexamethasone at a time course similar to that observed in steroid-induced glaucoma [15].
• Canine myocilin is associated with lipid modified by palmitic acid [16].

Other interactions of Myoc

• Reduced expression of Myoc was further confirmed by one-step real-time RT-PCR [4].
• MUTM-NEI/1 cells expressed mRNA for NCAM, aquaporin 1, myocilin/trabecular meshwork glucocorticoid-inducible protein, and alphaB-crystallin, which was increased after oxidative stress [17].

Analytical, diagnostic and therapeutic context of Myoc

• As a step in this development, we have investigated the expression pattern of Myoc transcripts in embryonic and adult mouse tissue using Northern blot and in situ hybridization analyses [12].
• Since TIGR is secreted, we assessed a possible role in inhibition of neuronal regeneration with an in vitro bioassay and found that this protein is a potent inhibitor of neurite outgrowth [18].
• Results of immunoprecipitation show that myocilin is a gamma-synuclein-interacting protein [13].
• Recombinant myocilin increases outflow resistance in perfused anterior segment organ cultures, while overexpression of myocilin after viral gene transfer appears to reduce outflow resistance [15].
• Amplification by PCR of this PPI1 variable region from a capsular serotype 17 strain and comparison of the sequence to TIGR serotype 4 strain sequence showed that Sp1051 is contained within an 11.3-kb segment of DNA flanked by 7-bp direct repeats within the serotype 4 strain which is not present in the serotype 17 strain [19].

References