Orofacial clefts, principally cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), are among the most common major birth defects, occurring in ~1/700 to 1/1000 live births in various populations around the world, ~70% as a sporadic, isolated abnormality. Such "non-syndromic" orofacial clefts act as complex traits, involving multiple genes and environmental risk factors. To date traditional genetic mapping approaches have identified only a few major susceptibility genes for non-syndromic orofacial clefts with certainty. Therefore, new approaches are clearly required. There is considerable evidence that orofacial malformations can occur at the extremes of the normal ranges of phenotypic variation of midfacial size and shape. Here we propose a novel approach to identify genes that regulate midfacial shape in mouse and human. We hypothesize that genes that are major contributors to normal orofacial size and shape will also have important roles in the occurrence of orofacial clefts. To identify such genes, we will perform detailed morphometric analysis of midfacial shape differences in innovative mouse strains as well as in select human populations, combining these studies with genetic analyses to identify genes that control major determinants of midfacial morphometries. Our studies have shown that specific inbred strains of mice have heritable differences in measurable parameters of facial shape. We will take advantage of a valuable new resource we have developed, the mouse "Collaborative Cross" (CC), to correlate heritable differences in facial shape among the 8 founder strains of the CC, along with select Recombinant Inbred lines and Recombinant Intercross (RIX), with detailed genetic mapping data for these mice. This approach will enable identification of quantitative trait loci (QTLs) that underlie these morphometric differences. We will complement our mouse studies with a similar analysis of humans, studying specific populations with different susceptibilities to orofacial clefts. These comparative studies will allow us to identify genes that underlie midfacial shape in humans. Finally, we will perform functional studies to assess how the genes we have identified can influence facial shape. Together, these studies should provide a basis for understanding the relationship between human facial morphogenesis and susceptibility to orofacial clefts, and for initiating studies of the functions of these genes in animal models relevant to human orofacial development.

Public Health Relevance

This proposal is submitted in specific response to an RFA "to develop projects to advance our understanding of normal craniofacial development and the genetic and environmental perturbations that lead to diseases and disorders." This proposal will study the genetic determinants of normal orofacial development in mouse and human, with the specific intent of investigating relationship of these genes to human orofacial clefts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DE020054-04
Application #
8258355
Study Section
Special Emphasis Panel (ZDE1-JH (24))
Program Officer
Scholnick, Steven
Project Start
2009-09-21
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$367,740
Indirect Cost
$107,613
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Manyama, Mange; Larson, Jacinda R; Liberton, Denise K et al. (2014) Facial morphometrics of children with non-syndromic orofacial clefts in Tanzania. BMC Oral Health 14:93
Hallgrimsson, Benedikt; Mio, Washington; Marcucio, Ralph S et al. (2014) Let's face it--complex traits are just not that simple. PLoS Genet 10:e1004724
Attanasio, Catia; Nord, Alex S; Zhu, Yiwen et al. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342:1241006
Parsons, Trish E; Schmidt, Eric J; Boughner, Julia C et al. (2011) Epigenetic integration of the developing brain and face. Dev Dyn 240:2233-44
Hochheiser, Harry; Aronow, Bruce J; Artinger, Kristin et al. (2011) The FaceBase Consortium: a comprehensive program to facilitate craniofacial research. Dev Biol 355:175-82