title: Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells.
abstract: MYOC encoding a 55kDa secretory glycoprotein named myocilin is closely linked to primary open-angle glaucoma (POAG). To understand a role played by MYOC in glaucoma, we examined the cellular fate of various mutant myocilins that were adenovirally expressed in human trabecular meshwork cells. Most myocilins with mutations such as G364V, Q368X, K423E, Y437H, and I477N were intrinsically stable, and appeared to have interactions with wild-type myocilin but not with stromelysin and thereby selectively inhibited the secretion of the former protein. The myocilins expressed were identified to be concentrated into fine punctate aggregates in endoplasmic reticulum, but never developed into the formation of aggresomes. In endoplasmic reticulum, the accumulation of the myocilins resulted in the upregulation of 78kDa glucose-regulated protein and protein disulfide isomerase. In addition, the expression of the myocilins led to deformed cellular morphology and diminished cell proliferation, an effect postulated to result in the dysfunction of trabecular cells that could be a cause of glaucoma. Therefore, our results support the statement that gain of function rather than haploinsufficiency is a critical mechanism for POAG in individuals with mutations on MYOC.
authors.affiliation: Department of Ophthalmology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Myung Kuk
authors.initials: MK
authors.lastname: Joe
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Sohn
authors.forename: Wonhee
authors.initials: W
authors.lastname: Hur
authors.forename: Younkyong
authors.initials: Y
authors.lastname: Moon
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Choi
authors.forename: Changwon
authors.initials: C
authors.lastname: Kee
mesh_terms: D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure*; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005902:Glaucoma, Open-Angle / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism* / Q000473:pathology; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014129:Trabecular Meshwork / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D011994:Recombinant Proteins; D000099179:Myocilin