title: Inefficient processing of an olfactomedin-deficient myocilin mutant: potential physiological relevance to glaucoma.
abstract: Mutations in TIGR/MYOC (myocilin), a secretory protein of unknown function, have been recently linked to glaucoma. Most known mutations map to the C-terminus, an olfactomedin-like domain. We have previously shown that, in contrast to the wild-type, a truncated form of myocilin lacking the olfactomedin domain is not secreted. In this study, we present evidence that the mutant protein is not correctly processed in the endoplasmic reticulum (ER) and accumulates into insoluble aggregates. In addition, we show that the presence of increasing amounts of mutant protein induces a fraction of the soluble, native myocilin to move to the insoluble fraction. Given the importance of such protein aggregates in the etiology of several aging-related diseases, we propose that olfactomedin-defective mutants might contribute to the pathology of glaucoma through a mechanism involving intracellular accumulation of misfolded proteins.
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: M
authors.initials: M
authors.lastname: Caballero
authors.forename: T
authors.initials: T
authors.lastname: Borrás
mesh_terms: D000256:Adenoviridae; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D003902:Detergents; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005822:Genetic Vectors; D005901:Glaucoma / Q000209:etiology* / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D012995:Solubility; D014129:Trabecular Meshwork / Q000378:metabolism; D014162:Transfection; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D003902:Detergents; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D011994:Recombinant Proteins; D000099179:Myocilin; C081451:olfactomedin