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

  • Author / Creator
    Ito, Yoko A
  • 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.  

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  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
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  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Medical Sciences-Medical Genetics
  • Supervisor / co-supervisor and their department(s)
    • Walter, Michael (Medical Genetics)
  • Examining committee members and their departments
    • Link, Brian (Cell Biology, Neurobiology, and Anatomy)
    • Underhill, Alan (Oncology)
    • Lehmann, Ordan (Ophthalmology)
    • McDermid, Heather (Biological Sciences)