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(Investigative Ophthalmology and Visual Science. 2001;42:145-152.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Evaluation of the Myocilin (MYOC) Glaucoma Gene in Monkey and Human Steroid-Induced Ocular Hypertension

John H. Fingert1, Abbot F. Clark2, Jamie E. Craig3,4, Wallace L. M. Alward1, Grant R. Snibson3, Marsha McLaughlin2, Linda Tuttle2, David A. Mackey3,4, Val C. Sheffield5,6 and Edwin M. Stone1

1 From the Departments of Ophthalmology and 2 Pediatrics, and 3 The Howard Hughes Medical Institute, The University of Iowa College of Medicine, Iowa City; 4 Glaucoma Research, Alcon Research, Ltd., Fort Worth, Texas; 5 Centre for Eye Research Australia, The University of Melbourne, Royal Victorian Eye and Ear Hospital; and the 6 Menzies Centre for Population Health Research, The University of Tasmania, Hobart, Australia.

PURPOSE. Glucocorticoid-induced ocular hypertension (the steroid response) may result in optic nerve damage that very closely mimics the pathologic course of primary open angle glaucoma (POAG). In addition, patients with glaucoma and their relatives are much more likely to exhibit the steroid response than unaffected individuals, suggesting a potential link between the steroid response and POAG. Recently, the expression of a gene (MYOC) in the trabecular meshwork was shown to be steroid-induced. MYOC variations thought to 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 involved in steroid-induced ocular hypertension.

METHODS. Seventy human steroid responders and 114 control subjects were screened for variations in the coding sequence and promoter of MYOC. Also, topical doses of dexamethasone (DEX) were administered to cynomolgus monkeys to determine their steroid responsiveness, and the MYOC orthologue was cloned from the cynomolgus monkey.

RESULTS. Overall, 109 instances of 20 different sequence variations were identified in the human myocilin gene. However, only four of these (each observed in a single individual) met the study criteria for a possible phenotype-altering variation. Three of these were present in steroid responders and one in a control patient, a distribution that was not statistically significant (P = 0.3). In addition, the allele frequency of a closely flanking marker was compared between the steroid responders and the control subjects, and no evidence for linkage disequilibrium was observed. Reproducible and reversible ocular hypertension was induced in approximately 40% of the monkeys treated with DEX, similar to that seen in man. Ten monkeys were screened for MYOC mutations with single-strand conformation polymorphism (SSCP) analysis. Overall, 37 instances of 13 different sequence variations were observed. Four of these changes met the study criteria for a possible phenotype-altering variation, and these were equally distributed between responder and nonresponder monkeys.

CONCLUSIONS. This study identified no statistically significant evidence for a link between MYOC mutations and steroid-induced ocular hypertension.




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