The overall goal of my work has been to gain a better understanding of Axenfeld-Rieger Syndrome (ARS), a human autosomal dominantly inherited mal-development of the anterior segment of the eye that is associated with glaucoma. By studying rare genetic causes of this complex disease we are gaining insight into the initial steps that ultimately lead to blindness. To achieve the goal of better understanding ARS, my research project had two parts. In the first part, I performed a retrospective clinical study in which I analyzed the glaucoma-related clinical presentation of ARS patients with FOXC1 and PITX2 defects. This study showed a good genotype-phenotype correlation which may be important for the physician in dealing with ARS patients. Patients with FOXC1 mutations had the mildest prognosis in glaucoma development, while patients with PITX2 defects and patients with FOXC1 duplication had a more severe prognosis in glaucoma development than patients with FOXC1 mutations. I tried to determine the best treatment for glaucoma in these patients. Unfortunately, in this study, current medical therapies did not successfully lower intraocular pressure or prevent progression of glaucoma in ARS patients with FOXC1 or PITX2 alterations. This clinical study also provided useful diagnostic criteria to identify the gene responsible for ARS. The second part of the project was to study the gene regulatory pathways of the PITX2 gene, mutations of which cause ARS. PITX2 is a transcription factor that regulates the expression of genes in the eye. The discovery of direct downstream targets of PITX2 is necessary for understanding the genetic mechanisms underlying complex, highly regulated processes such as development and underlying heritable human disorders. To find direct target genes of PITX2, I have used a recently developed method: the hormone receptor (HR)-inducible expression system for transcription factors coupled microarray analysis. The results obtained using this method have involved PITX2 in control of cellular stress. Recent investigations have suggested significant roles for cellular stress in glaucoma pathology. Understanding the control of these key aspects of cell function will have profound implications for understanding and treating the glaucoma that is the most clinically serious consequence of mutations of PITX2.

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