title: Altered secretion of a TIGR/MYOC mutant lacking the olfactomedin domain.
abstract: TIGR/MYOC, a novel 504 amino acids (aa) protein of unknown function, has recently been linked to glaucoma. The protein is both intra- and extracellular and most known mutations map to its C-terminus, an olfactomedin-like domain. To investigate the properties of a TIGR/MYOC peptide lacking this important domain, we constructed a replication-deficient adenovirus with the first 344 aa and over-expressed the truncated protein in primary human trabecular meshwork cells and perfused human anterior segment cultures. The truncated mutant contains the entire N-terminus plus 98 aa of the olfactomedin-like domain. We found that the delivered truncated mutant accumulates inside the cell, reduces secretion of endogenous TIGR/MYOC and induces an increase in outflow facility at 48 h post-infection. Based on these findings, we hypothesize that TIGR/MYOC might have a dual role in trabecular meshwork function. This dual role might be that of an intracellular modulator of vesicular transport as well as that of a secreted protein involved in extracellular matrix conformation. Both functions could have a direct effect in maintaining aqueous humor outflow facility.
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Wadsworth Building, Erwin Road, P.O. Box 3802, Durham, NC 27710, USA.
authors.forename: M
authors.initials: M
authors.lastname: Caballero
authors.forename: L L
authors.initials: LL
authors.lastname: Rowlette
authors.forename: T
authors.initials: T
authors.lastname: Borrás
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D000869:Anterior Eye Segment / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000494:pharmacology; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D005901:Glaucoma / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007429:Intraocular Pressure; D008969:Molecular Sequence Data; D009154:Mutation; D009924:Organ Culture Techniques; D010477:Perfusion; D011994:Recombinant Proteins / Q000494:pharmacology; D012212:Rheology; D014129:Trabecular Meshwork / Q000378:metabolism; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D011994:Recombinant Proteins; D000099179:Myocilin; C081451:olfactomedin