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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Liberman, Ellen S
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University of Iowa
Schools of Medicine
Iowa City
United States
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Saadi, Irfan; Toro, Rafael; Kuburas, Adisa et al. (2006) An unusual class of PITX2 mutations in Axenfeld-Rieger syndrome. Birth Defects Res A Clin Mol Teratol 76:175-81
Espinoza, Herbert M; Ganga, Mrudula; Vadlamudi, Usha et al. (2005) Protein kinase C phosphorylation modulates N- and C-terminal regulatory activities of the PITX2 homeodomain protein. Biochemistry 44:3942-54
Katz, L A; Schultz, R E; Semina, E V et al. (2004) Mutations in PITX2 may contribute to cases of omphalocele and VATER-like syndromes. Am J Med Genet A 130A:277-83
Mintz-Hittner, Helen A; Semina, Elena V; Frishman, Laura J et al. (2004) VSX1 (RINX) mutation with craniofacial anomalies, empty sella, corneal endothelial changes, and abnormal retinal and auditory bipolar cells. Ophthalmology 111:828-36
Trembath, Dimitri G; Semina, Elena V; Jones, Douglas H et al. (2004) Analysis of two translocation breakpoints and identification of a negative regulatory element in patients with Rieger's syndrome. Birth Defects Res A Clin Mol Teratol 70:82-91
Mutti, Donald O; Semina, Elena; Marazita, Mary et al. (2002) Genetic loci for pathological myopia are not associated with juvenile myopia. Am J Med Genet 112:355-60
Saadi, I; Semina, E V; Amendt, B A et al. (2001) Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276:23034-41
Semina, E V; Brownell, I; Mintz-Hittner, H A et al. (2001) Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 10:231-6
Hjalt, T A; Amendt, B A; Murray, J C (2001) PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome. J Cell Biol 152:545-52
Semina, E V; Mintz-Hittner, H A; Murray, J C (2000) Isolation and characterization of a novel human paired-like homeodomain-containing transcription factor gene, VSX1, expressed in ocular tissues. Genomics 63:289-93

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