Non-Syndromic Cleft Palate in Mice

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DESCRIPTION (provided by applicant): Development of the mammalian secondary palate is a complex and critical process that in man can be easily perturbed leading to the common and distressing birth defect, cleft palate (CP). Clefts of the primary and/or secondary palates are consistently included among the more common congenital anomalies occurring in man. Even though the combination of cleft lip with/or without cleft palate (CLIP) is more commonly seen, isolated CP can account for approximately one-third of the documented cases. Isolated CP is considered to be an etiologically heterogeneous trait with an important genetic contribution. While CP can be associated with more that 350 characterized disorders, more than 50% of cases of CP occur as isolated (sporadic) and thought to be free of other anomalies (non-syndromic). Our long-term objectives focus on identifying genetic determinants that directly and/or indirectly (i.e. genetic susceptibility and multifactorial causes) contribute to the failure of mammalian secondary palate formation (using animal models) and to better understand the roles that these genes play at the molecular level during normal secondary palate formation. Similarities in palate development between humans and mice have allowed the later to be an important model organism for studying normal and defective palatogenesis. Transgene insertion mutagenesis can facilitate the identification of developmentally important genes through non-homologous disruption of endogenous genes. We have been investigating four separate lines of transgenic mice that develop autosomal recessive nonsyndromic cleft palate involving a least three distinct loci that localize to chromosomes 3 and 4. The focus of this research project is to characterize the interval of genomic DNA disrupted by these transgene insertions as a prelude to identifying the disrupted genes responsible for cleft palate in these mice.