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Contribution of FOXC1 to the development of Axenfeld-Rieger Syndrome and glaucoma Open Access


Other title
Axenfeld-Rieger Syndrome
Oxidative stress
Type of item
Degree grantor
University of Alberta
Author or creator
Ito, Yoko A
Supervisor and department
Walter, Michael (Medical Genetics)
Examining committee member and department
Lehmann, Ordan (Ophthalmology)
Underhill, Alan (Oncology)
McDermid, Heather (Biological Sciences)
Link, Brian (Cell Biology, Neurobiology, and Anatomy)
Medical Sciences-Medical Genetics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Axenfeld-Rieger syndrome (ARS) is a rare developmental disease that affects structures in the anterior segment of the eye. Approximately 50% of ARS patients develop glaucoma, a progressively blinding condition. Although glaucoma is an aging-related disease, ARS patients usually have earlier-onset of the disease. Mutations in Forkhead box C1 (FOXC1) are associated with ARS. FOXC1 is a member of the Forkhead box family of transcription factors that share a highly conserved DNA binding domain known as the Forkhead domain (FHD). Two missense mutations, L130F and W152G, which are both located within the FOXC1 FHD were molecularly characterized. Overexpression experiments in cell culture showed that both mutations resulted in compromised ability of the mutant proteins to localize to the nucleus, bind DNA, and transactivate a reporter gene. Immunofluorescence experiments showed that the L130F mutant proteins are able to form potentially protective aggresomes. In addition, the role of FOXC1 in the stress response pathway was examined. Using human trabecular meshwork (HTM) cells, HSPA6, a member of the HSP70 family of proteins, was validated to be a direct target gene of FOXC1. HSPA6 protein appears to be an anti-apoptotic protein that is only detected under severe oxidative stress conditions. Interestingly, the FOXC1 transcription factor appears to be stress-responsive itself since exposure to H2O2 resulted in decreased FOXC1 RNA and protein levels. Decreased FOXC1 levels increased apoptotic cell death. Thus, FOXC1 may continue to play a role in the adult eye by maintaining homeostasis. Mutations in FOXC1 may compromise the ability of TM cells to respond to oxidative stress due to dysregulation of anti-apoptotic genes such as HSPA6. The TM cells of ARS patients with FOXC1 mutations may be more vulnerable to environmental stresses including mechanical and oxidative stresses. As a result, increased TM cell death may occur, resulting in the dysregulation of aqueous humor drainage and elevation of IOP, which is a major risk factor for developing glaucoma. TM cell death may occur earlier in ARS patients with FOXC1 mutations, resulting in the earlier onset of glaucoma in this subset of ARS patients.  
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Ito YA and Walter MA. (2013). Genetics and Environmental Stress Factor Contributions to Anterior Segment Malformations and Glaucoma. Shimon Rumelt (Ed.). Glaucoma - Basic and Clinical Aspects (pp.27-56). InTech.Ito YA, Footz TK, Berry FB, Mirzayans F, Yu M, Khan AO, and Walter MA. Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. (2009). Invest Ophthalmol Vis Sci. 50(8):3573-3579.

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