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

Allan R. Shepard, Nasreen Jacobson, J. Cameron Millar, Iok Hou Pang, H. Thomas Steely, Charles C. Searby, Val C. Sheffield, Edwin M. Stone, Abbot F. Clark

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)609-617
Number of pages9
JournalHuman Molecular Genetics
Volume16
Issue number6
DOIs
StatePublished - 15 Mar 2007

Fingerprint Dive into the research topics of 'Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure'. Together they form a unique fingerprint.

  • Cite this