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Abstract #17504 Published in IGR 9-2
Glaucoma-causing myocilin mutants require the peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure
Shepard AR; Jacobson N; Millar JC; Pang I-H; Steely HT; Searby CC; Sheffield VC; Stone EM; Clark AFHuman Molecular Genetics 2007; 16: 609-617
Glaucoma is a leading cause of worldwide irreversible visual impairment and blindness and is a clinically and genetically heterogenous group of optic neuropathies. Specific mutations in the myocilin (MYOC) gene cause primary open angle glaucoma (POAG) with varying age-of-onset and degree of severity. We show a mutation-dependent, gain-of-function association between human myocilin and the peroxisomal targeting signal type 1 receptor (PTS1R). There was correlation between the glaucoma phenotype and the specific MYOC mutations, with the more severe early-onset POAG mutations having a higher degree of association with PTS1R. Expression of human myocilin glaucomatous mutations in mouse eyes causes elevated intraocular pressure, 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.
Dr. A.R. Shepard, Glaucoma Research, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA. allan.shepard@alconlabs.com
Classification:
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)