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Editors Selection IGR 7-2

Basic research: Myocilin

Comment by Ernst Tamm on:

13762 Temperature sensitive secretion of mutant myocilins, Vollrath D; Liu Y, Experimental Eye Research, 2006; 82: 1030-1036

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Mutations in myocilin are responsible for GLC1A-linked glaucoma, which accounts for about 4% of cases with primary open-angle glaucoma. The expression of myocilin in the trabecular meshwork (TM) is extremely high suggesting an important function for aqueous humor outflow. So far, neither the biochemical functions of normal myocilin nor that of its glaucoma-causing mutants have been identified. Several laboratories provided evidence that mutated myocilin is not secreted from cells neither in vitro nor in vivo. In previous work, Vollrath et al. (362) contributed that a specific mutant form of myocilin is poorly secreted at 37°C, probably because of abnormal protein folding, and that prolonged expression of the mutant protein results in cell killing. Culturing

Myocilin-induced glaucoma is a protein conformational disease, which results in TM cell death

the cells at lower temperatures, a condition known to facilitate protein folding, enhances secretion and reverses cytotoxic effects. In this new contribution, they extend their original observation to a larger number of myocilin mutants showing that temperature-sensitive secretion is a property of most of the mutants. The results support the hypothesis that myocilin-induced glaucoma is a protein conformational disease, which results in TM cell death. While this is an excellent piece of laboratory work, it is highly desirable to confirm the hypothesis of this study in an in vivo situation, or even in affected glaucoma patients. Myocilin has been identified as a glaucoma causing gene almost ten years ago. It is quite surprising that up to today, there are no data available about the TM cell phenotype of affected patients expressing mutant myocilin. It is for this reason that it remains unclear, if TM cells in these patients do also not secrete mutant myocilin, and if this lack of secretion really kills TM cells and causes deterioration of the aqueous humor outflow pathways.

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