Myocilin, trabecular meshwork inducible glucocorticoid response (TIGR), also known asMYOC, is aprotein which in humans is encoded by theMYOCgene.[5][6] Mutations inMYOC are a major cause ofglaucoma.
Thecytogenetic location of humanMYOCgene is on thelong (q) arm ofchromosome 1, specifically at position 24.3 (1q24.3).[7] The gene's molecular location starts at 171,635,417bp and ends at 171,652,63bp onchromosome 1 (Annotation: GRCh38.p12)(assembly).
Myocilin is a protein with a weight of 55 kDa (504amino acid) and an overall acidic property, the product of the first gene that has been linked toPrimary Open Angle Glaucoma (POAG).[5]
The protein is made up of the two folding domains, theleucine zipper-likedomain at theN-terminal and an olfactomedin-like domain at theC-terminal. The domain at the N-terminal is known to have 77.6% homology to themyosin heavy chain ofDictyostelium discoideum and 25% homology with the cardiacβ-myosin heavy chain.[6][8] The gene encodes three differentexons, each consisting of different structural and functional domains.[9]
The N-terminal is encoded by exon 1 and contains theleucine zipperstructural motif, which consists of 50 amino acid residues (117-169 amino acids).[8] The motif is found on anα-helix, which enhances the binding of the protein. The name of the domain arises due to the occurrence ofleucine as well as,arginine repeats periodically on theα-helix.[9][8] The leucine zipper domain also contains the myocilin-myocilin interactions between amino acid residues 117-166.[10] Exon 2 encodes the central region of the protein at amino acid residues 203-245 however, no structural or functional domains are found in this region. Exon 3 encodes the C-terminal of myocilin and has been found to contain the olfactomedin-like domain.[11] The olfactomedin is an extracellular matrix protein with no defined role but is abundantly found in theolfactory neuroepithelium.[11] In the myocilin protein, the domain consists of a singledisulfide bond which connects twocysteine residues (245 and 433 amino acids).[12]
Myocilin is specifically located in the ciliary rootlet and basal body which connects to the cilium of photoreceptor cells in therough endoplasmic reticulum. The intracellularly distributed protein is processed in theendoplasmic reticulum (ER) and in secreted into theaqueous humour.[13] It is only imported into the trabecular meshwork of the mitochondria. In theextracellular space, it appears in the trabecular meshwork cells through an unconventional mechanism which is associated with exosome-like vesicles. Myocilin localises in theGolgi apparatus ofcorneal fibroblasts and Schlemm's canal endothelial cells.[14][15]
Severalisoforms are produced due topost-translational modifications processes, includingglycosylation andpalmitoylation.[16] The gene undergoes N-glycosylation at the Asn-Glu-Ser site (57–59 amino acids) and O-glycosylation throughout the protein at the Ser-Pro, Pro-Ser, Thr-Xaa-Xaa-Pro, Ser-Xaa-Xaa-Xaa-Pro sites.[16][17]
Myocilin also undergoes aproteolytic cleavage in the endoplasmic reticulum at residue Arg-226. The cleavage process iscalcium dependant and results in two fragments.[18] One fragment contains the C-terminal olfactomedin-like domain (35 kDa), and the other contains the N-terminal leucine zipper-like domain (20 kDa).[9][18]
MYOC encodes the protein myocilin. The precise function of myocilin is unknown, but it is normally secreted into theaqueous humor of the eye. MYOC mutations, which cause myocilin to accumulate in the cells of the trabecular meshwork are a common cause of glaucoma. Most MYOC mutations identified in glaucoma patients are heterozygous and are confined to the olfactomedin domain, which is encoded by exon 3.[8]
Myocilin is believed to have a role incytoskeletal function.MYOC is expressed in many ocular tissues, including thetrabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulatingintraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angleglaucoma.[19]
Scientific research has found the function of myocilin to be linked with other proteins, making it part of aprotein complex. The isoform of thecytochrome P450 protein, 1B1 (CYP1B1) has shown interaction with myocilin.CYP1B1 is also found in several structures so the eye including, trabecular meshwork and the ciliary body.[20]
Differing mutations in theMYOC gene have been reported to associate withglaucoma 1, open angle (GLC1A) andglaucoma 3, primary congenital (GLC3A).
Glaucoma 1 is a form of primary open-angle glaucoma (POAG), which is characterized based on a specific pattern of defects in theoptic nerve, thus causing visual defects.[5][21] The disease causes an angle in the anterior chamber of the eye to be left open, which in turn causes theintraocular pressure to be increased. Although an increase in the intraocular pressure is a major factor for glaucoma, the disease can occur independently of the intraocular pressure.[21] Furthermore, the damage done to the optical nerve has been classified as irreversible because no symptoms of the disease are apparent (asymptomatic) until its last stages.[21]
Glaucoma 3 arises due to mutations in the distinct genetic loci ofMYOC. This mutation contributes to GLC3A through digenic inheritance with theCYP1B1 protein.[20] The mutation gives rise to anautosomal recessive form of primary congenital glaucoma (PCG). The disease initiates at birth or in early childhood due to the increase in intraocular pressure, large ocular globes (buphthalmos) and corneal edema. The progression of the disease causes defects in the trabecular meshwork and anterior chamber angle of the eye preventing the drainage from theaqueous humor.[20]
| Race | Occurrence frequency (%) |
|---|---|
| African | 4.44 |
| Asian | 3.30 |
| Caucasian | 3.86 |
MYOC contains a signal sequence for secretion and is secreted into the aqueous humor of the eye by the trabecular meshwork. Mutations inMYOC are found in 4% of adult-onset primary open-angle glaucoma and >10% of juvenile-onset primary open-angle glaucoma. Overexpression or underexpression ofMYOC does not cause glaucoma. However, theMYOC gene also contains a signal sequence, which is normally not functional, that directs intracellular proteins toperoxisomes. Glaucoma-associated mutations activate that signal sequence and direct myocilin to peroxisomes, where they accumulate in the cell, instead of being secreted. Decreased secretion and increased accumulation appear to be the initial steps in myocilin-associated glaucoma.[23]
A study employing an iterative pocket and ligand-similarity based approach to virtual ligand screening predicted small molecule binders for the olfactomedin domain of human myocilin. The predictions were subsequently assessed by differential scanning fluorimetry.[24]
MYOC has been shown tointeract with the following proteins:[16][25][26]
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