Worldwide, glaucoma is the leading irreversible cause for blindness. Primary open angle glaucoma (POAG) is the most common subset and by the year 2020 it is estimated that approximately 60 million people will be affected . This neurodegenerative disorder is characterised by progressive excavation of the optic disc with corresponding loss of the visual field. It is also frequently associated with elevated intraocular pressure. Although the prevalence of POAG increases with age, a subset of patients are diagnosed with a juvenile onset form (JOAG).
In 1997 Stone and colleagues identified mutations in the myocilin gene (OMIM: 601652; formerly: trabecular meshwork-induced glucocorticoid response gene or TIGR) in families affected by autosomal dominant POAG . Myocilin maps to the GLC1A locus at 1q24.3-q25.2. Subsequent work has revealed that mutations in myocilin account for approximately 3% of unselected POAG cases .
Myocilin has three exons and contains two major homology domains, an N-terminal myosin-like domain and a C-terminal olfactomedin-like domain . It encodes a predicted 504 amino acid polypeptide and the majority of disease-causing variations are clustered in the olfactomedin homology domain of the third exon.
Myocilin is expressed ubiquitously in the eye and despite numerous descriptions of nonsense and premature termination myocilin mutations, haploinsufficiency of the myocilin protein has been excluded as the primary disease mechanism . Interestingly POAG is not induced through genetically increasing or decreasing wild-type myocilin expression . However, a gain-of-function disease model has been suggested through the identification of mutant forms of the myocilin protein being misfolded and aggregating in the endoplasmic reticulum of trabecular meshwork cells . Trabecular meshwork cells are essential for the homeostatic regulation of aqueous humour in the eye and their disruption causes elevated intraocular pressure. In February 2007, Shepard and colleagues revealed that there is a mutation-dependent, gain-of-function association between human myocilin and the peroxisomal targeting signal type 1 receptor (PTS1R) . It has been hypothesised that specific myocilin mutations may lead to different amounts of MYOC misfolding, with corresponding varying degrees of recognition by the ubiquitin degradation pathway. A greater opportunity for mutant MYOC to interact with PTS1R may allow for poorer clearance from the trabecular meshwork endoplasmic reticulum and greater trabecular cell dysfunction, culminating in a higher IOP phenotype .
For additional information regarding myocilin readers are direct to the special issue of Experimental Eye Research (Vol 82:6) which in Honour of Jon R. Polansky (March 30, 1948 - April 9, 2005) contains six directly relevant articles.
This resource is described in the following reference: Hewitt AW, Mackey DA, Craig JE. Myocilin allele-specific glaucoma phenotype database. Hum Mutat. 2008; 29(2):207-11..
For other locus specific databases please visit the Human Genome Variation Society website.
1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006; 90(3):262-267.
2. Stone EM, Fingert JH, Alward WL et al. Identification of a gene that causes primary open angle glaucoma. Science 1997; 275(5300):668-670.
3. Fingert JH, Stone EM, Sheffield VC, Alward WL. Myocilin glaucoma. Surv Ophthalmol 2002; 47(6):547-561.
4. Tamm ER. Myocilin and glaucoma: facts and ideas. Prog Retin Eye Res 2002; 21(4):395-428.
5. Gould DB, Miceli-Libby L, Savinova OV et al. Genetically increasing MYOC expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell Biol 2004; 24(20):9019-9025.
6. Shepard AR, Jacobson N, Millar JC et al. Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure. Hum Mol Genet. 2007 Mar 15;16(6):609-17.