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裂形成的分子致病机制。面裂，包括唇裂和腭裂，是常见的出生缺陷，影响全球约1/700的活产婴儿。面部裂患者要接受广泛的手术、牙科、语言和心理治疗，通常从婴儿期到青少年期持续多年。尽管与此类出生缺陷相关的频繁发生和广泛的医学治疗，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，面部裂的遗传易感性，试图通过家庭和病例对照研究确定易感基因座已被证明是不一致的。这项研究计划已经确定了一个独特的动物模型，研究的病因和发病机制的口面裂。自发突变Dancer的纯合子小鼠表现出唇裂和腭裂。Dancer杂合子小鼠表现出易裂倾向：这些突变小鼠在与不同遗传背景异交后表现出唇裂，并且它们还表现出对致畸剂诱导的裂的易感性显著增加。初步研究已经将Dancer突变定位到2.2 Mb基因组区域，该区域与人类染色体区域同线，与裂易感性有很强的连锁关系。因此，Dancer突变小鼠提供了一个独特的机会，以确定一个裂易感基因和表征的分子致病过程，包括基因-基因和基因-环境的相互作用，导致orofacial clefting。本申请提出了两个具体目标：（1）通过候选基因分析和定位克隆的组合表征Dancer突变的分子基础;和（2）使用微阵列、实时定量PCR、原位杂交和生物信息学分析的组合表征Dancer突变体中促成裂发病机制的基因表达谱。这些研究将大大增加我们对口面裂形成的致病机制的理解，并将导致更好地诊断，治疗和/或预防口面裂的方法的发展。

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.