OBJECTIVE: Mutations in myocilin (may cause either juvenile open angle glaucoma (JOAG) or adult-onset primary open angle glaucoma (POAG).encodes a glycoprotein that is normally secreted from trabecular meshwork cells that regulate intraocular pressure. Priortransgenic rodent, and organ culture experiments have suggested that abnormal accumulation of MYOC protein within trabecular meshwork cells is a key step in glaucoma pathophysiology. We investigated the pathogenesis ofglaucoma by examining a donor eye from a patient with JOAG caused by a Tyr437Hismutation. MYOC) MYOC in vitro, MYOC MYOC
DESIGN: Case-control, immunohistochemical study of a donor eye from a patient with JOAG caused by a Tyr437Hismutation and age-matched control donor eyes. MYOC
SUBJECTS: An eye from a 59-year-old male with JOAG caused by a Tyr437Hismutation and eyes from five donors (ages 51-66) with no known ocular disease were examined. MYOC
METHODS: Frozen fixed sections of the iridocorneal angle were prepared from the donor eyes of theglaucoma patient and control eyes. We used antibodies directed against MYOC, collagen IV, and BiP/GRP78 as well as wheat germ agglutinin and concanavalin A lectins to localize MYOC protein in the trabecular meshwork. MYOC
MAIN OUTCOME MEASURE: Qualitative comparison of MYOC protein labeling and localization in the trabecular meshwork of donor eyes from a glaucoma patient with amutation and from control subjects. MYOC
RESULTS: Using immunohistochemistry, we detected more abundant MYOC protein within the trabecular meshwork of theglaucoma patient's eye than in control eyes. We further localized MYOC protein within the trabecular meshwork cells of theglaucoma patient's eye by co-labeling with the endoplasmic reticulum (ER) marker GRP78 (BiP). Little to no MYOC was identified within the trabecular meshwork cells of control eyes. Minimal extracellular MYOC was detected in bothglaucoma eyes and control eyes. MYOC MYOC MYOC
CONCLUSIONS: This is the first histopathological analysis of an eye from a glaucoma patient with amutation. Furthermore, this analysis supports our model of MYOC-associated glaucoma, in whichmutations cause abnormal intracellular retention of MYOC within the ER of trabecular meshwork cells as a key step towards development of glaucoma. MYOC MYOC
