Myocilin and glaucoma: facts and ideas

Abstract

Mutations in the MYOC gene that encodes for myocilin are causative for some forms of juvenile and adult-onset primary open-angle glaucoma (POAG). Myocilin is a secreted 55–57 kDa glycoprotein that forms dimers and multimers. Characteristic structural motifs include a myosin-like domain, a leucine zipper region and an olfactomedin domain. Most of the mutations that have been identified in patients with POAG are localized in the olfactomedin domain, which is highly conserved among species. In the eye, myocilin is expressed in high amounts in the trabecular meshwork (TM), sclera, ciliary body and iris, and at considerable lower amounts in retina and optic nerve head. Secreted myocilin is present in the aqueous humor. In the TM, myocilin is found within the cytoplasm of TM cells and in the juxtacanalicular region in association with fibrillar extracellular matrix components. Since patients with mutations in myocilin may have high intraocular pressures, the role of myocilin for aqueous humor outflow has been investigated and conflicting results have been obtained. Recombinant myocilin increases outflow resistance in perfused anterior segment organ cultures, while overexpression of myocilin after viral gene transfer appears to reduce outflow resistance. 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. Other factors that induce myocilin expression are transforming growth factor-β and mechanical stretch. Promoter elements that are important for the glucocorticoid induction have not been identified, but it has been shown that upstream stimulatory factor is critical for the basal promoter activity of MYOC. Mice with a targeted disruption of the myocilin gene do not express a phenotype, indicating that the glaucomatous phenotype in humans is not because of a loss-of-function effect. Experimental studies show that mutated myocilin is not secreted, but appears to accumulate in the cells. Such an accumulation might interfere with TM function and lead to impaired outflow resistance, but, so far, experimental evidence for such a scenario is lacking. In addition, the normal function(s) of myocilin is (are) still elusive.

Introduction

Glaucoma, which is characterized by a continuous degeneration of the axons in the optic nerve head (ONH), is one of the leading causes of blindness throughout the world (Thylefors et al., 1995). The major risk factor for the axonal loss in glaucoma is an intraocular pressure (IOP) that is too high for the health of the optic nerve. In primary open-angle glaucoma (POAG), the most common form of glaucoma, elevated IOP results from an increase in aqueous humor outflow resistance in the trabecular meshwork (TM). Despite decades of research, the mechanisms that generate trabecular outflow resistance and/or that are causative for its increase in POAG have been difficult to understand and are still largely unclear. For this reason, the discovery that mutations in the gene encoding for myocilin are responsible for some forms of POAG (Stone et al., 1997) has had tremendous impact on glaucoma research. For the first time, a specific gene product had been identified that can be causative for glaucoma. Patients harboring mutations in myocilin may suffer from very high IOP (Wiggs et al., 1995; Johnson et al., 1996; Alward et al., 1998), and it seemed clear that an understanding of the function of myocilin might provide the long-sought key to finally understand the pathogenesis of POAG. At present, after almost 5 years of research on myocilin, considerable progress has been made in understanding the structure and localization of myocilin, as well as mechanisms that control its expression. Nevertheless, the specific function of myocilin and its role in POAG have remained elusive.