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Editors Selection IGR 7-2

Basic research: Myocilin

Comment by Douglas Johnson on:

12050 Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice, Zillig M; Wurm A; Grehn FJ et al., Investigative Ophthalmology and Visual Science, 2005; 46: 223-234

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This elegant study by Zillig et al. (94) addresses two long-standing questions in glaucoma research: 1. Does excess normal myocilin cause glaucoma? 2. How could mutant myocilin cause glaucoma? A clever use of transgenic mice caused cloned myocilin genes to be expressed only in the lens of the eye. The desired myocilin genes - either the normal 'wild type' or a mutation at position 437 - were placed into fertilized mouse eggs. The genes were linked to a tissue specific promoter that is only expressed in the lens of the eye: betaB1-crystallin. This prevented the genes from being expressed in every cell of the body, which could potentially be lethal for the animal. In this way the lenses became factories for production of myocilin. Of interest, the genes for human myocilin- not mouse myocilin- were used. The techniques worked, but did not cause glaucoma. Normal wild type myocilin was indeed produced by the lens, and was found in the aqueous at levels almost 5x those in human aqueous. This did not raise IOP. This overexpression of myocilin did not harm the lens nor cause problems in the trabecular meshwork: histologic examination was normal. Mutant myocilin was also produced in the lens, but was not found in the aqueous. In keeping with current thought, the mutant myocilin remained in the endoplasmic reticulum of the cells, unable to exit because of the misfolding of the mutant molecule. This eventually destroyed the lens: cataracts developed, and the continued production of the mutant eventually caused the lens to enlarge and rupture, causing some mutant myocilin to appear in the aqueous. What can a mouse tell us of man? Although mice do not spontaneously develop POAG, and thus must differ fundamentally from the human, experimental work in mice confirms the molecular and cellular processing pathways predicted in human cells. Only a living system, with the rich array of growth factors, proteins, regulatory pathways, and immune reactions not present in cell culture models, can ultimately tell us about how tissues and organs function. This study takes us a giant step along this pathway.

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