Non-secretion of mutant proteins of the glaucoma gene myocilin in culturedtrabecular meshwork cells and in aqueous humor

Until recently, very little was known about the molecular mechanisms respon sible for the development of glaucoma, a leading cause of blindness worldwi de. Mutations in the glaucoma gene myocilin (MYOC, GLC1A) are associated wi th elevated intraocular pressure and the development of autosomal dominant juvenile glaucoma and a subset of adult-onset glaucoma. MYOC is expressed i n the trabecular meshwork (TM), a tissue responsible for drainage of aqueou s humor from the eye, and the tissue involved in elevated intraocular press ure associated with glaucoma. To better understand the role of MYOC in glau coma pathogenesis, we examined the expression of normal and mutant myocilin in cultured ocular (TM) and non-ocular cells as well as in the aqueous hum or of patients with and without MYOC glaucoma. Normal myocilin was secreted from cultured cells, but very little to no myocilin was secreted from cell s expressing five different mutant forms of MYOC. In addition, no mutant my ocilin was detected in the aqueous humor of patients harboring a nonsense M YOC mutation (Q368X), Co-transfection of cultured cells with normal and mut ant myocilin led to suppression of normal myocilin secretion. These studies suggest that MYOC glaucoma is due either to insufficient levels of secrete d myocilin or to compromised TM cell function caused by congestion of the T M secretory pathway.