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Human Molecular Genetics, 2001, Vol. 10, No. 2 117-125
© 2001 Oxford University Press

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

Nasreen Jacobson1,+, Michael Andrews2,+, Allan R. Shepard1, Darryl Nishimura3, Charles Searby2, John H. Fingert4, Greg Hageman4, Robert Mullins4, Beverly L. Davidson5, Young H. Kwon4, W.L.M. Alward4, Edwin M. Stone4, Abbot F. Clark1,§ and Val C. Sheffield2,3

1Glaucoma Research, Alcon Research Ltd, 6201 South Freeway, Fort Worth, TX 76134, USA, 2Howard Hughes Medical Institute, 3Department of Pediatrics, 4Department of Ophthalmology and 5Departments of Internal Medicine and Neurology, University of Iowa, Iowa City, IA, USA

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

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +1 817 551 4909; Fax: +1 817 568 7645; Email: abe.clark@alconlabs.com


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