May 2008
Volume 49, Issue 13
ARVO Annual Meeting Abstract  |   May 2008
Increased Stability of a Mutated PITX2 Protein May Cause Axenfeld-Reiger Syndrome
Author Affiliations & Notes
  • M. Acharya
    Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
  • T. Footz
    Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
  • F. Idrees
    Developmental Biology Unit, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, University College London, London, United Kingdom
  • M. A. Walter
    Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
  • Footnotes
    Commercial Relationships  M. Acharya, None; T. Footz, None; F. Idrees, None; M.A. Walter, None.
  • Footnotes
    Support  Canadian Institute of Health Research and Alberta Heritage Foundation for Medical Research
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5110. doi:
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      M. Acharya, T. Footz, F. Idrees, M. A. Walter; Increased Stability of a Mutated PITX2 Protein May Cause Axenfeld-Reiger Syndrome. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5110. doi:

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Mutations in the homeobox transcription factor PITX2 result in Axenfeld-Reiger syndrome (ARS) which is associated with anterior segment dysgenesis and an increased risk of glaucoma. Analyses were performed to assess functions of mutation-bearing PITX2 proteins, and to correlate function with phenotypic severity in the patients. We here, mapped domains within PITX2, determined the functional consequences of missense mutations outside of the homeodomain of PITX2, and a recently reported mutation (R43W) in the N-terminal arm of the homeodomain.

Methods: : Wild type and mutant PITX2A proteins were expressed in human trabecular meshwork cells. Analyses of recombinant proteins were done for subcellular localisation, DNA binding capacity, transcription activity and half-life determination.

Results: : A series of protein truncations were constructed to determine the functional domains within PITX2. PITX2 was found to have 2 transactivation domains, 2 inhibitory domains as well as the PITX2 homeodomain. Recombinant PITX2A proteins carrying the L105V and N108T mutations showed little or no defects in subcellular localization, DNA-binding capability or reporter transactivation, whereas R43W resulted in severely-reduced DNA-binding and transcriptional activation abilities. The half-life of normal PITX2A was determined to be 70 min while for the mutant R90C and N108T it was 119 min and 143 min respectively.

Conclusions: : PITX2 is a multi-domain protein with both activation and inhibitory domains indicating PITX2 is under complex regulation. We discovered that PITX2 mutations outside the homeodomain do not have defects in DNA binding, nuclear localization or transactivation. However, the N108T mutant appears to result in a PITX2 molecule with increased half-life. Increased stability of mutated PITX2 resulting in prolonged/disregulated PITX2 activity, therefore may underlie ARS in this patient.

Keywords: mutations • transcription factors • anterior segment 

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