Human development is a complex process involving multiple gene interactions at various stages of embryogenesis and with important environmental overlays. In the last few years, the role of transcription factors in early development and the impact that disruptions in these genes can have on normal structures has become increasingly evident. We have recently identified the human RIEG1 (PITX2) gene as a novel bicoid- class homeobox gene responsible for Rieger syndrome, which has anterior chamber defects, dental hypoplasia and umbilical abnormalities as primary manifestations. A second member of this family (PITX3) has just been identified in our laboratory in which a mutation causes the disorder anterior segment mesenchymal dysgenesis (ASMD) and also autosomal dominant cataracts. In this proposal, we will expand on our studies of these transcription factors, through identification of additional human ocular and systemic disturbances caused by abnormalities in these genes and by detailed studies of the genes developmental cascade. Specific goals of the project will include: 1) additional characterization of the Rieger class genes, including their DNA structure, the identification of new class members and of genes homologous to the recognized regulatory sequences. Further characterization of families and individuals, with a particular focus on those whose phenotype includes glaucoma and cataracts will also be carried out; 2) expressed-based studies will be performed that will include tissue-specific studies involving the mouse model and the identification of genes that interact with Rieger-class genes; 3) the use of transgenic animals as a model system for the study of epistatic interactions, including the development of knockout mice for two of Rieger-class genes and the initiation of complementation studies using Rieger-related genes and genes with similar or complementary expression patters. The outcome of this project will be an expansion of our understanding of the causes of the common conditions, glaucoma and cataracts, as well as a detailed understanding of the developmental biology of a new class of homeobox genes shown to be critical in ocular and systemic development. Models will be developed that can be used for studies of gene-gene and gene-environment interactions to further our insights into basic biology, therapeutics and prevention. The correlation of expanded phenotypes with specific mutations and the ability to study these for gene-gene and gene-environment interactions affords an opportunity for a comprehensive understanding of a new class of homeobox genes for their role in human birth defects and adult disease.
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