The long-term goal of the proposed research is to understand the molecular pathogenic mechanisms underlying facial cleft formation. Facial clefts, including cleft lip and cleft palate, are common birth defects that affect approximately 1 in 700 live births worldwide. Individuals with facial clefts undergo extensive surgical, dental, speech and psychological therapies that usually last for many years from infancy through the teenage years. Despite the frequent occurrence and extensive medical treatment associated with such birth defects, the causes and the pathogenic processes that lead to cleft lip and/or cleft palate are not well understood. Whereas there is strong evidence for genetic predisposition to facial clefting, attempts at identifying susceptibility loci via family and case control studies have proved inconsistent. This research program has identified a unique animal model for studying the etiology and pathogenic mechanisms of orofacial clefting. Mice homozygous for a spontaneous mutation, Dancer, exhibit cleft lip and cleft palate. Dancer heterozygous mice show predisposition to clefting: these mutant mice show cleft lip after outcrossing to a different genetic background and they also exhibit significantly increase susceptibility to teratogen-induced clefting. Preliminary studies have mapped the Dancer mutation to a 2.2 Mb genomic region, which is syntenic to a human chromosomal region with strong linkage to cleft susceptibility. Thus, the Dancer mutant mice provide a unique opportunity to identify a cleft predisposing gene and to characterize the molecular pathogenic processes, including gene-gene and gene-environment interactions that lead to orofacial clefting.
Two specific aims are proposed for this application: (1) to characterize the molecular basis of the Dancer mutation through a combination of candidate gene analysis and positional cloning; and (2) to characterize the gene expression profiles contributing to cleft pathogenesis in the Dancer mutants using a combination of microarray, real-time quantitative PCR, in situ hybridization and bioinformatic analyses. These studies will greatly increase our understanding of the pathogenic mechanisms underlying orofacial cleft formation and will lead to development of methods for better diagnosis, treatment and/or prevention of orofacial clefting. ? ?
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