The effects of myocilin expression on functionally relevant trabecular meshwork genes: a mini-review

Abstract

Myocilin is a secreted glaucoma-associated protein, specifically induced by dexamethasone in human trabecular meshwork cells, where it was discovered. Myocilin is expressed in several tissues of the body, but it causes disease only in the eye. The protein contains two domains: an N-terminal region with significant homologies to nonmuscle myosin, and a C-terminal region, which is similar to the olfactomedin proteins. Forty percent of myocilin undergoes an intracellular endoproteolytic cleavage by calpain II, a calcium-dependent cysteine protease, which releases the 2 domains. The protein is known to interact with intracellular and extracellular matrix proteins, and some is released into the extracellular space associated with exosomes. Myocilin mutations are linked to glaucoma and induce elevated intraocular pressure. Most of the glaucoma-causative mutations map to the olfactomedin domain, which appears to be a critical domain for the function of the protein. Myocilin mutants are misfolded, aggregate in the endoplasmic reticulum, and are not secreted. Overexpression of myocilin and of its mutants in primary human trabecular meshwork cells triggers changes in the expression of numerous genes, many of which have been known to be involved in mechanisms important for the physiology and pathology of the tissue. Here we review recent studies from our laboratory and those of others that deal with trabecular meshwork genes, which are altered by the overexpression of wild-type and glaucoma-causative mutant myocilin genes.

FIG. 1.

Venn maps of genes of the trabecular meshwork altered by overexpression of wild-type and 4 glaucoma-causative myocilin mutants. Hybridization was conducted on Affymetrix GeneChips (n=17) and analyzed with GeneSpring 10 software. Nonredundant gene lists had cutoff fold-change values of≥and ≤1.5. (A) Number of genes altered in each of the mutants that overlap with genes altered by the wild-type. (B) Number of genes altered in all mutants.

FIG. 2.

Heat maps depicting changes induced by myocilin mutants on the WNT pathway and Unfolded Protein Response trabecular meshwork genes. Gene lists for each pathway were custom-generated by literature review. Each row represents the fold change (Adeno.myocilin.mutant over Adeno.Null) for a single gene in each of the 4 mutants. Each column represents the fold changes for all genes of the category in one myocilin mutant. The fold change for each gene is visually represented by a color, which is given by the scale bar on the right. Gray cells indicate that the expression of the given gene was below the signal intensity cutoff value and was considered absent. Modified from reference 6 with permission.