title: Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure.
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.
authors.affiliation: Glaucoma Research, Alcon Research, Ltd, Fort Worth, TX 76134, USA. allan.shepard@alconlabs.com
authors.forename: Allan R
authors.initials: AR
authors.lastname: Shepard
authors.forename: Nasreen
authors.initials: N
authors.lastname: Jacobson
authors.forename: J Cameron
authors.initials: JC
authors.lastname: Millar
authors.forename: Iok-Hou
authors.initials: IH
authors.lastname: Pang
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Steely
authors.forename: Charles C
authors.initials: CC
authors.lastname: Searby
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Abbot F
authors.initials: AF
authors.lastname: Clark
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000503:physiopathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007429:Intraocular Pressure; D051379:Mice; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000074435:Peroxisome-Targeting Signal 1 Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D000099179:Myocilin; C000614264:PEX5 protein, human