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Human Molecular Genetics Advance Access originally published online on February 22, 2007
Human Molecular Genetics 2007 16(6):609-617; doi:10.1093/hmg/ddm001
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure

Allan R. Shepard1,*,{dagger}, Nasreen Jacobson1,{dagger}, J. Cameron Millar1, Iok-Hou Pang1, H. Thomas Steely1, Charles C. Searby3, Val C. Sheffield2,3, Edwin M. Stone2,4 and Abbot F. Clark1

1 Glaucoma Research, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA, 2 Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA, 3 Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA and 4 Department of Ophthalmology, University of Iowa, Iowa City, IA 52242, USA

* To whom correspondence should be addressed. Tel: +1 8176152312; Fax: +1 8175687553; Email: allan.shepard{at}alconlabs.com

Received January 3, 2007; Accepted January 9, 2007

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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