alexa Transgenic mice expressing the Tyr437His mutant of human myocilin protein develop glaucoma.
Genetics

Genetics

Advancements in Genetic Engineering

Author(s): Zhou Y, Grinchuk O, Tomarev SI

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Abstract PURPOSE: To developed a genetic mouse model of primary open-angle glaucoma induced by expression of mutated human myocilin in transgenic mice and to test whether expression of mutated human myocilin in the eye angle structures produces more significant damage to the eye than does mutated mouse myocilin. METHODS: Recombineering in Escherichia coli was used to introduce the Tyr437His point mutation into a BAC carrying the full-length human MYOCILIN (MYOC) gene and long flanking regions. This BAC was used to produce transgenic mice. The expression of myocilin in the iridocorneal angle tissues and aqueous humor was studied by immunohistochemistry and Western blot analysis. Intraocular pressure was measured noninvasively with a fiber optic transducer. Retinal ganglion cells were retrograde labeled with fluorescent gold, and counted 5 days after labeling. RESULTS: BAC transgenic mice expressed elevated levels of myocilin in tissues of the iridocorneal angle. Expression of mutated myocilin induced its intracellular accumulation and prevented secretion of both mutated and wild-type myocilin into the aqueous humor. Transgenic mice demonstrated a moderate elevation of intraocular pressure, which was more pronounced at night than in daytime. In the peripheral retina, transgenic mice lost 20\% of the retinal ganglion cells and 55\% of large retinal ganglion cells. Axonal degeneration was observed at the periphery of the optic nerve. CONCLUSIONS: Expression of equivalent levels of mutated human or mouse myocilin in the eyes of transgenic mice produce comparable pathologic changes that are similar to those observed in patients with glaucoma.
This article was published in Invest Ophthalmol Vis Sci and referenced in Advancements in Genetic Engineering

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