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 (PITX) 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). In this proposal, we will expand our studies of these transcription factors, through identification of additional human craniofacial 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 gene homologous to the recognized regulatory sequences. Further characterization of families and individuals, with a particular focus on those whose phenotype includes craniofacial anomalies will also be carried out; 2) expression-based studies will be performed that will included tissue-specific studies involving the mouse model; 3) the use of transgenic animals as a model systems for the study of epistatic interactions, including the development of knockout mice for two of the 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 facial structural defects, as well as a detailed understanding of the developmentally biology of a new class of homeobox genes shown to be critical in 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 interaction affords a opportunity for a comprehensive understanding of a new class of homeobox genes for their role in human birth defects and adult disease. This project will directly interact with Project 3 (Russo) which will study protein-protein interactions of the PITX genes and interface with projects 4 and 5 and the clinical and molecular cores, as well.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Comprehensive Center (P60)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Iowa City
United States
Zip Code
Haworth, Simon; Shungin, Dmitry; van der Tas, Justin T et al. (2018) Consortium-based genome-wide meta-analysis for childhood dental caries traits. Hum Mol Genet 27:3113-3127
Govil, Manika; Mukhopadhyay, Nandita; Weeks, Daniel E et al. (2018) Novel caries loci in children and adults implicated by genome-wide analysis of families. BMC Oral Health 18:98
Yang, Jie; Zhu, Wei; Chen, Jiansong et al. (2014) Genome-wide two-marker linkage disequilibrium mapping of quantitative trait loci. BMC Genet 15:20
Beaty, T H; Taub, M A; Scott, A F et al. (2013) Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. Hum Genet 132:771-81
Skare, Oivind; Jugessur, Astanand; Lie, Rolv Terje et al. (2012) Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts. Ann Hum Genet 76:221-36
Wehby, G L; Tyler, M C; Lindgren, S et al. (2012) Oral clefts and behavioral health of young children. Oral Dis 18:74-84
Schneider, Galen B; Zaharias, Rebecca; Seabold, Denise et al. (2011) Integrin-associated tyrosine kinase FAK affects Cbfa1 expression. J Orthop Res 29:1443-7
Larjava, H; Koivisto, L; Häkkinen, L et al. (2011) Epithelial integrins with special reference to oral epithelia. J Dent Res 90:1367-76
Shaffer, J R; Wang, X; Feingold, E et al. (2011) Genome-wide association scan for childhood caries implicates novel genes. J Dent Res 90:1457-62
Jugessur, Astanand; Shi, Min; Gjessing, Håkon Kristian et al. (2010) Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia. PLoS One 5:e11493

Showing the most recent 10 out of 83 publications