Variations in the Myocilin Gene in Patients With Open-Angle Glaucoma

Abstract

To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects. Methods: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism. Results: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele. Conclusions: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity. Clinical Relevance: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma.

Dexamethasone-Induced Ocular Hypertension in Mice

“…24,26,27 MYOC was discovered as the first gene responsible for juvenile open-angle glaucoma and a subset of POAG. 25,28,29 The current function of MYOC is unknown, but it has been suggested that MYOC might play a role in development of GC-induced OHT and secondary glaucoma. MYOC expression and OHT induction occur in response to GCs, and both follow similar time-course and dose-response curves.…”

“…28 Approximately 3% to 5% of POAG patients have mutations in MYOC. 29,30 The exact role of wild-type (WT) MYOC is not completely understood. Various genetic strategies, including knockout, knock-in, or transient expression of transgenic mutant MYOC, were tested in mouse models.…”

Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma

“…Mutations in MYOC were not identified in patients with steroidinduced ocular hypertension (2,13). These previous studies do not rule out the possibility that mutations in genes responsible for the regulation of MYOC result in abnormally high MYOC levels after steroid use and that this causes glaucoma.…”

“…Disease-associated mutations have been identified in the myocilin gene, MYOC (14,43). Studies from a broad range of ethnic backgrounds generally agree that MYOC mutations are responsible for approximately 3% of adult-onset POAG and a greater proportion of juvenile-onset open-angle glaucoma (2,14). Despite this, neither the normal function(s) of MYOC nor how MYOC mutations result in IOP elevation and glaucoma has been defined.…”

“…Some investigators suggest that MYOC promoter variants may influence the progression of glaucoma (10,11,29), while others disagree with this conclusion (2). Since human patients are currently offered genetic testing based on the presence of noncoding variants, the issue is very important.…”