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Y. Zhou, O. Grinchuk, E. F. Wawrousek, S. I. Tomarev; Transgenic Mice Expressing the Tyr437his Mutant Human Myocilin Protein Develop Glaucoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4033.
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© ARVO (1962-2015); The Authors (2016-present)
To examine changes in the eyes of transgenic (Tg) mice expressing human MYOCILIN (MYOC) with the Tyr437His point mutation, which is known to induce one of the most severe forms of glaucoma.
Recombineering in E. coli was used to introduce the Tyr437His point mutation into a BAC carrying full-length human MYOC. This BAC was used to produce Tg mice. The expression of MYOC in the irido-corneal angle tissue and aqueous humor was studied by immunohistochemistry, and western blotting using antibodies that recognize both human and mouse MYOC. Intraocular pressure (IOP) was measured non-invasively with a fiber optic transducer. Retinal ganglion cells (RGCs) were retrograde labeled with FluroGold, and counted 5 days after labeling. Morphological changes in the eye of Tg animals were analyzed using semi-thin plastic sections.
MYOC levels in tissues of the irido-corneal angle were 3 fold higher in Tg mice than in control (Wt) mice. Expression of the mutated human MYOC completely blocked secretion of normal mouse MYOC into aqueous humor. IOP in the eyes of 18 month-old Tg animals (12.0 ± 1.3 mmHg, n=34) was about 2 mmHg higher than that in the eyes of Wt animals (n=30) during the day time and about 3.5 mmHg higher (18.3 ± 1.7 vs 14.9 ± 0.9 mmHg) during the night time. No obvious defects were observed in the irido-corneal tissues of the eyes of Tg mice. Tg mice demonstrated a 20% decrease in the number of RGCs in the peripheral retina, compared to Wt littermates. Large RGCs were specifically affected, as demonstrated by immunostaining with antibody SMI-32 that specifically recognizes large RGCs. Thinning of the neuronal fiber layer, reduced number of neuronal fibers, and degeneration of axons in the optic nerve were also observed in Tg mice.
Expression of the Tyr437His mutant human MYOC in the eyes of Tg mice induces changes similar to those observed in human glaucoma patients, and with a similar developmental time course. These mice represent a genetic mouse model of open-angle glaucoma.
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