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Human Molecular Genetics Advance Access originally published online on April 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 11 1193-1204
DOI: 10.1093/hmg/ddh128
Human Molecular Genetics, Vol. 13, No. 11 © Oxford University Press 2004; all rights reserved

Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma

Yuhui Liu and Douglas Vollrath*

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305-5120, USA

Received February 27, 2004; Accepted March 31, 2004

Glaucoma is a progressive blinding disease characterized by gradual loss of vision due to optic neuropathy and retinal ganglion cell death. Increased intraocular pressure is a common feature of glaucoma that is thought to arise from an increased resistance to outflow of aqueous humor through the trabecular meshwork. Mutations of the myocilin gene are one cause of autosomal dominant juvenile- and adult-onset primary open angle glaucoma, but the mechanism by which mutant myocilins cause disease is poorly understood. We have found that disease-causing myocilin mutants are misfolded, are highly aggregation-prone and accumulate in large aggregates in the endoplasmic reticulum (ER) of human embryonic kidney cells and differentiated primary human trabecular meshwork (HTM) cells. In HTM cells, Pro370Leu mutant myocilin is not secreted under normal culture conditions and prolonged expression results in abnormal cell morphology and cell killing. Culturing HTM cells at 30°C, a condition known to facilitate protein folding, promotes secretion of mutant myocilin, normalizes cell morphology and reverses cell lethality. Our results indicate that myocilin-associated glaucoma is an ER storage disease and suggest a progression of events in which chronic expression of misfolded, non-secreted myocilin leads to HTM cell death, trabecular meshwork dysfunction and, ultimately, a dominant glaucoma phenotype. The beneficial effects of facilitating folding and secretion of mutant myocilin suggest a new type of treatment for this form of glaucoma.

* To whom correspondence should be addressed. Tel: +1 6507233290; Fax: +1 6507237016; Email: vollrath{at}genome.stanford.edu


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