Genetic Basis of Cleft Lip and Palate

描述（由申请人提供）：拟议研究的长期目标是了解面部裂缝形成的分子致病机制。包括唇裂和腭裂在内的面部裂是一种常见的出生缺陷，全世界每700个活产婴儿中就有1个受到影响。患有唇裂的人需要接受广泛的手术、牙科、语言和心理治疗，这些治疗通常从婴儿期到青少年时期持续多年。尽管这种出生缺陷的发生频率和广泛的医学治疗相关，但导致唇裂和/或腭裂的原因和致病过程尚不清楚。虽然有强有力的证据表明遗传倾向于面部裂，但通过家庭和病例对照研究确定易感性位点的尝试被证明是不一致的。本研究项目确定了一种独特的动物模型，用于研究唇腭裂的病因和发病机制。自发突变的纯合小鼠，舞蹈家，表现出唇裂和腭裂。舞者杂合小鼠易发生唇裂：这些突变小鼠在与不同遗传背景的异种杂交后出现唇裂，而且它们对致畸物诱导的唇裂的易感性也显著增加。初步研究已将Dancer突变定位到一个2.2 Mb的基因组区域，该区域与人类染色体区域一致，与裂裂易感性有很强的联系。因此，舞蹈家突变小鼠提供了一个独特的机会来鉴定一个唇裂易感基因，并表征分子致病过程，包括导致唇裂的基因-基因和基因-环境相互作用。这一应用的两个具体目的是：(1)通过候选基因分析和定位克隆的结合来表征Dancer突变的分子基础；(2)结合微阵列技术、实时定量PCR技术、原位杂交技术和生物信息学分析技术，研究导致舞蹈家突变体裂口发病的基因表达谱。这些研究将大大增加我们对口腔颌面部裂形成的致病机制的理解，并将导致更好的诊断、治疗和/或预防口腔颌面部裂的方法的发展。

DESCRIPTION (provided by applicant): 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.