Glaucoma is the second leading cause of irreversible blindness in the United States and is the leading cause of blindness in African Americans. Cupping or excavation of the optic nerve, which sends the visual signal from the photoreceptors in the eye to the brain, is a chief feature of glaucoma. A similar excavated appearance of the optic nerve is also the primary clinical sign of other congenital malformations of the eye including optic nerve head coloboma, optic pit, and morning glory disc anomaly collectively termed cavitary optic disc anomaly (CODA). Clinical similarities between CODA and glaucoma have suggested that these conditions may have overlapping pathophysiology. Although risk factors are known, such as the elevated intraocular pressure (IOP) observed in some glaucoma subjects, the biological pathways and molecular events that lead to excavation of the optic disc in glaucoma and in CODA are incompletely understood, which has hindered efforts to improve diagnosis and treatment of these diseases. Consequently, there is a critical need to clarify the biological mechanisms that lead to excavation of the optic nerve, which will lead to improvements in our understanding of these important disease processes. Because of their similar clinical phenotypes and the limited therapy geared at lowering IOP in glaucoma patients, our central hypothesis is that genes involved in Mendelian forms of CODA would also be involved in a subset of glaucoma cases and may provide insight into glaucomatous optic neuropathy. The purpose of my research project has been to identify and functionally characterize the gene that causes congenital autosomal dominant CODA in a multiplex family with 17 affected members. The gene that causes CODA was previously mapped to chromosome 12q14 and following screening of candidate genes within the region that did not yield any plausible coding sequence mutations, a triplication of a 6KB segment of DNA upstream of the matrix metalloproteinase 19 (MMP19) gene was subsequently identified using comparative genomic hybridization arrays and qPCR. This copy number variation (CNV) was present in all affected family members but absent in unaffected family members, a panel of 78 normal control subjects, and the Database of Genomic Variants. In a case-control study of singleton CODA subjects, CNVs were also detected; we detected the same 6KB triplication in 1 of 24 subjects screened. This subject was part of another 3-generation autosomal dominant CODA pedigree where affected members each have the same CNV identified in the larger CODA pedigree. A separate case-control study with 172 glaucoma cases (primary open angle glaucoma = 84, normal tension glaucoma = 88) was evaluated for MMP19 CNVs, however none were detected. Although our cohort of CODA patients is small limiting our ability to accurately determine the proportion of CODA caused by MMP19 mutations, our data indicates that the MMP19 CNV is not an isolated case and additional CODA subjects may have MMP19 defects. Because of the location of the CNV, we evaluated its effect on downstream gene expression with luciferase reporter gene assays. These assays revealed that the 6KB sequence spanned by the CNV in CODA subjects functioned as a transcriptional enhancer; in particular, a 773bp segment had a strong positive influence (8-fold higher) on downstream gene expression. MMP19, a largely understudied gene, was further characterized by expression studies in the optic nerve and retina. Using frozen sections from normal donor eyes, we demonstrated that MMP19 is predominantly localized to the optic nerve head in the lamina cribrosa region with moderate labeling in the postlaminar region, and weak labeling in the prelaminar region and retina. We also evaluated MMP19 expression in relation to the cell types that populate the optic nerve such as astrocytes and retinal ganglion cells. The pattern of expression is consistent with MMP19 being a secreted protein accumulating in the extracellular spaces and basement membranes of the optic nerve. Our studies have identified the first gene associated with CODA and future research is focused on recapitulating CODA phenotypes in animal models and assessing the mechanism of MMP19 involvement during development.