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Editors Selection IGR 8-3

Genetics

Comment by John Fingert on:

12150 Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids Arg²²⁶ and Ile²²⁷, Aroca-Aguilar JD; Sanchez-Sanchez F; Ghosh S et al., Journal of Biological Chemistry, 2005; 280: 21043-21051

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Mutations in the myocilin gene have been associated with juvenile open angle glaucoma and approximately 4% of primary open angle glaucoma. Prior studies investigating the pathogenesis of myocilin-associated glaucoma have indicated that mutations in this gene somehow decrease the solubility and secretion of the encoded myocilin protein. In a comprehensive set of experiments with transiently transfected cell lines, Aroca-Aguilar et al. (450) have demonstrated that recombinant wild-type myocilin protein is specifically cleaved between amino acid 226 and 227 and that this processing is hindered by mutations that have been previously associated with glaucoma.

Analysis of the culture media of cells transfected with wild-type myocilin identified full-length myocilin protein (55 kDa) and a C-terminal fragment (35 kDa) among secreted proteins. Purification and sequencing of the 35 kDa fragment showed that it is composed of amino acids 227 through 504 and contains the olfactomedin domain in which glaucoma-causing mutations have been identified. The 35 kDa fragment of myocilin protein was also detected in aqueous humor and extracts from iris and ciliary body indicating that the cleavage also occurs in human tissue. These studies demonstrate that myocilin protein is specifically cleaved between amino acid 226 and 227 and that the cleavage product along with unprocessed protein is secreted. When cell lines were transfected with myocilin harboring mutations previously associated with glaucoma (E323K, Q368X, P370L, or D380A), cleavage of the encoded proteins was significantly reduced or absent. Among the missense myocilin mutations, those associated with the most severe glaucoma phenotype exhibited the strongest inhibition of protein cleavage. Aroca-Aguilar and coworkers have discovered an important step in the biological pathway in which mutations in myocilin contribute to the development of glaucoma

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