Glaucoma-associated myocilin: a better understanding but much more to learn

Abstract

Over a decade has passed since myocilin was identified as the first gene linked to early and late-onset primary open-angle glaucoma. During this time, considerable effort has been put forth to understand the functional role myocilin has in normal and glaucomatous eyes. Myocilin is expressed in many ocular and non-ocular tissues, is found in both intracellular and extracellular spaces, and has been linked to elevations in intraocular pressure. Mutations in the myocilin gene that have been associated with glaucoma appear to confer a gain-of-functional activity rather than loss of function. Unfortunately, what the normal function of myocilin is and how alterations in the function can confer a glaucoma phenotype have yet to be elucidated. We will review the current understanding of myocilin with special emphasis on the structural makeup of the myocilin gene and protein, its possible physiological roles internal and external to ocular cells, the regulation of intraocular pressure as evidenced through the use of perfusion culture systems and animal models, and as a causative agent in some forms of glaucoma.

Fig. 1

Structure of human myocilin. Analysis of myocilin's primary sequence identifies several structural motifs: a signal peptide sequence [amino acid (aa)1−32], a helix-turn-helix (HtH) domain (aa18−58), two coil–coil (CC) domains (aa74−110 and aa118−186), and a C-terminal globular domain (aa230−504) that contains homology to olfactomedins (aa326−501), a protein family involved in many diverse functions. Asterisks represent leucine amino acids involved in leucine zipper. Number sign denotes N-glycosylation site. Arrow indicates calpain II cleavage site.

Fig. 2

Glaucoma-causing mutations in myocilin. Over 70 myocilin glaucoma-causing mutations have been identified in myocilin, with >90% found in exon 3 that codes for the olfactomedin-homology domain of myocilin. Gene structure is shown on right. Numbers under the exons denote codon location in gene sequence.