Identification of Chemical Correctors for the Trafficking Defect of Mutant SLC4A11 Open Access
- Other title
- Type of item
- Degree grantor
University of Alberta
- Author or creator
Chiu, Anthony M.
- Supervisor and department
Casey, Joseph (Biochemistry, Physiology)
- Examining committee member and department
Cordat, Emmanuelle (Physiology)
Lehmann, Ordan (Ophthalmology and Visual Sciences, Medical Genetics)
Leslie, Elaine (Physiology)
Department of Physiology
- Date accepted
- Graduation date
Master of Science
- Degree level
Congenital Hereditary Endothelial Dystrophy, Harboyan Syndrome and Fuchs’ Endothelial Corneal Dystrophy are three forms of heterogeneous, genetic corneal blindness. Mutations in the membrane protein SLC4A11 have been found to cause cases of these diseases. Most mutations in SLC4A11 cause the protein to misfold and become retained in the endoplasmic reticulum. The loss of function of SLC4A11 is thought to give rise to the symptoms of these diseases. Currently, the only permanent therapy for these diseases is corneal transplant. A pharmacological therapy is needed to better treat these diseases caused by SLC4A11. Screening techniques for the assessment of small molecule correctors is the first step toward a pharmacological therapy. A high throughput screening assay was developed to detect SLC4A11 at the plasma membrane. This technique could also be applied to other plasma membrane proteins. A small scale screen revealed that three non-steroidal anti-inflammatory drugs rescue the trafficking defect of some mutations of SLC4A11. Glafenine was effective in rescuing the trafficking defect in all three mutations screened. Functional analysis revealed that these mutants, when rescued to the plasma membrane, retained functional activity. These data suggest that glafenine may be a viable therapeutic for some cases of endothelial corneal dystrophies.
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