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A. R. Shepard, N. Jacobson, J. C. Millar, I.-H. Pang, H. T. Steely, C. C. Searby, V. C. Sheffield, E. M. Stone, A. F. Clark; Glaucoma-Causing Myocilin Mutants Require the Peroxisomal Targeting Signal-1 Receptor (PTS1R) to Elevate Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4806.
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Glaucoma is a leading cause of worldwide irreversible visual impairment and blindness and is a clinically and genetically heterogenous group of optic neuropathies. We sought to determine how and why specific mutations in the myocilin (MYOC) gene cause primary open angle glaucoma (POAG) with varying age-of-onset and degree of severity.
Interaction of the C-terminal half of myocilin with PTS1R was determined by yeast two-hybrid analysis and confirmed by mammalian two-hybrid analysis and co-immunoprecipitation. Visualization of intracellular mutant myocilin localization was done by confocal microscopy analysis. Effects of adenoviral expressed myocilin on IOP were determined in mice.
We show a mutation-dependent, gain-of-function association between human myocilin and PTS1R. There was correlation between the glaucoma phenotype and the specific MYOC mutations, with the more severe early-onset POAG mutations (e.g. Y437H and G364V) having a higher degree of association with PTS1R. Expression of human myocilin glaucomatous mutants in mouse eyes causes significantly (p<0.001) elevated intraocular pressure (IOP), which is a major phenotype of MYOC glaucoma.
This is the first demonstration of a disease resulting from mutation-induced exposure of a cryptic signaling site that causes mislocalization of mutant protein to peroxisomes and the first disease-gene-based animal model of human POAG.
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