Evaluation of the myocilin (MYOC) glaucoma gene in monkey and human steroid-induced ocular hypertension

PURPOSE. Glucocorticoid-induced ocular hypertension (the steroid response) may result in optic nerve damage that very closely mimics the pathologic co urse of primary open angle glaucoma (POAG). In addition, patients with glau coma and their relatives are much more likely to exhibit the steroid respon se than unaffected individuals, suggesting a potential link between the ste roid response and POAG. Recently, the expression of a gene (MYO) in the tra becular meshwork was shown to be steroid-induced. MYOC variations thought t o be disease-causing also were found in 3% to 5% of POAG cases. The purpose of this study was to determine whether some variations in MYOC might be in volved in steroid-induced ocular hypertension. METHODS. Seventy human steroid responders and 114 control subjects were scr eened for variations in the coding sequence and promoter of MYOC. Also, top ical doses of dexamethasone (DEX) were administered to cynomolgus monkeys t o determine their steroid responsiveness, and the MYOC orthologue was clone d from the cynomolgus monkey. RESULTS. Overall, 109 instances of 20 different sequence variations were id entified in the human myocilin gene. However, only four of these (each obse rved in a single individual) met the study criteria for a possible phenotyp e-altering variation. Three of these were present in steroid responders and one in a control patient, a distribution that was not statistically signif icant (P = 0.3). In addition, the allele frequency of a closely flanking ma rker was compared between the steroid responders and the control subjects, and no evidence for linkage disequilibrium was observed. Reproducible and r eversible ocular hypertension was induced in approximately 40% of the monke ys treated with DM, similar to that seen in man. Ten monkeys were screened for MYOC mutations with single-strand conformation polymorphism (SSCP) anal ysis. Overall, 37 instances of 13 different sequence variations were observ ed. Four of these changes met the study criteria for a possible phenotype-a ltering variation, and these were equally distributed between responder and nonresponder monkeys. CONCLUSIONS. This study identified no statistically significant evidence fo r a link between MYOC mutations and steroid-induced ocular hypertension.