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John H. Fingert, Abbot F. Clark, Jamie E. Craig, Wallace L. M. Alward, Grant R. Snibson, Marsha McLaughlin, Linda Tuttle, David A. Mackey, Val C. Sheffield, Edwin M. Stone; Evaluation of the Myocilin (MYOC) Glaucoma Gene in Monkey and Human Steroid-Induced Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2001;42(1):145-152.
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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
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