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Editors Selection IGR 8-1

Basic research: Myocillin

Comment by Doug Vollrath on:

13517 Mutated mouse and human myocilins have similar properties and do not block general secretory pathway, Malyukova I; Lee HS; Fariss RN et al., Investigative Ophthalmology and Visual Science, 2006; 47: 206-212

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Myocilin mutations account for 3-4% of primary open angle glaucoma and 10-33% of juvenile open angle glaucoma. Mutant myocilins appear to cause glaucoma through acquisition of a property not present in the wild-type protein, a mechanism known as a gain-of-function. Creation of an animal model of myocilin-associated glaucoma would be an important advance, allowing detailed studies of disease pathogenesis and testing of potential therapies. As a prelude to constructing a mouse model of myocilin-associated glaucoma, Malyukova et al. (61) compared the cell biological properties of glaucoma-causing mutant human myocilins to mouse myocilins engineered to contain homologous mutations. They found that the human and mouse mutant myocilins had similar properties when expressed in monkey kidney cells, including inefficient secretion and retention in the endoplasmic reticulum, complex formation with wild-type myocilin, and stimulation of mutant protein secretion by lower temperature culturing. In contrast, the introduction of glaucoma-associated mutations into proteins related to myocilin (optimedins A and B) did not necessarily lead to inhibition of their secretion. Consistent with earlier work, while co-expression of mutated mouse myocilin inhibited secretion of the wild-type protein, it did not inhibit secretion of three unrelated proteins, suggesting that mutant myocilins do not cause glaucoma through a general block of the secretory pathway. This is the first extensive study of the properties of a non-human myocilin containing mutations homologous to those found in individuals with glaucoma. The results indicate a degree of generality in the mechanism of mutant myocilin misfolding and aggregation across species, but the mechanism does not extend to all myocilin-related proteins. These results support the feasibility of creating a mouse model of myocilin-associated glaucoma.

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