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Temperature sensitive secretion of mutant myocilins
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305-5120, USA. vollrath@genome.stanford.edu
Experimental Eye Research
|November 22, 2005
Summary
Most glaucoma-causing myocilin mutants show temperature-sensitive secretion, with less severe glaucoma linked to better secretion. This suggests glaucoma is a protein misfolding disease, offering new therapeutic targets.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Glaucoma is often caused by mutant myocilin proteins that misfold and accumulate in the endoplasmic reticulum.
- Previous work showed P370L mutant myocilin impairs trabecular meshwork cells, but lower temperatures improve its secretion and cell survival.
Purpose of the Study:
- To investigate if temperature-sensitive secretion is a common characteristic of various myocilin missense mutants.
- To correlate the degree of secretion at reduced temperatures with the severity of associated glaucoma phenotypes.
Main Methods:
- Transiently expressed wild-type and 15 myocilin missense mutants in HEK 293 cells.
- Cultured cells at either 37°C or 30°C to assess protein secretion via immunoblotting.
Main Results:
- 14 out of 15 myocilin mutants exhibited enhanced secretion at 30°C compared to 37°C.
- A general inverse correlation was observed between mutant myocilin secretion at 30°C and glaucoma phenotype severity.
- Mutants with high secretion at 30°C (e.g., T377M, G364V) are linked to milder glaucoma, while poorly secreted mutants (e.g., P370L, I477N) are linked to more severe forms.
Conclusions:
- Temperature-sensitive secretion is a characteristic of most olfactomedin-domain myocilin mutants.
- The findings support the hypothesis that myocilin-induced glaucoma is a protein conformational disease.
- Enhancing mutant protein folding presents a potential therapeutic strategy for glaucoma.
