title: Expression of mutated mouse myocilin induces open-angle glaucoma in transgenic mice.
abstract: We developed a genetic mouse model of open-angle glaucoma by expression of mutated mouse myocilin (Myoc) in transgenic (Tg) mice. The Tyr423His point mutation, corresponding to the severe glaucoma-causing Tyr437His mutation in the human MYOC gene, was introduced into bacterial artificial chromosome DNA encoding the full-length mouse Myoc gene and long flanking regions. Both wild-type (Wt) and Tg animals expressed Myoc in tissues of the irido-corneal angle and the sclera. Expression of mutated Myoc induced the accumulation of Myoc in cell cytoplasm and prevented its secretion into the extracellular space. The levels of ATPase-1 were reduced in the irido-corneal angle of Tg mice compared with Wt animals. Tg mice demonstrated a moderate elevation of intraocular pressure, the loss of approximately 20% of the retinal ganglion cells (RGCs) in the peripheral retina, and axonal degeneration in the optic nerve. RGC depletion was associated with the shrinkage of their nuclei and DNA fragmentation in the peripheral retina. Pathological changes observed in the eyes of Tg mice are similar to those observed in glaucoma patients.
authors.affiliation: Section of Molecular Mechanisms of Glaucoma, Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Senatorov
authors.forename: Irina
authors.initials: I
authors.lastname: Malyukova
authors.forename: Robert
authors.initials: R
authors.lastname: Fariss
authors.forename: Eric F
authors.initials: EF
authors.lastname: Wawrousek
authors.forename: Srividya
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
authors.forename: Stanislav
authors.initials: S
authors.lastname: Tomarev
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D003315:Cornea / Q000378:metabolism / Q000503:physiopathology; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005123:Eye / Q000378:metabolism* / Q000503:physiopathology; D005136:Eye Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006023:Glycoproteins / Q000235:genetics*; D007498:Iris / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology; D017354:Point Mutation / Q000235:genetics*; D012162:Retinal Degeneration / Q000209:etiology / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000473:pathology; D000099179:Myocilin
chemical_list: D000251:Adenosine Triphosphatases; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin