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隙形成的分子致病机制。面部裂隙，包括唇裂和腭裂，是常见的出生缺陷，全世界大约每700名活产儿中就有1人受到影响。患有面部裂隙的人要接受广泛的外科、牙科、言语和心理治疗，这些治疗通常从婴儿期到十几岁持续很多年。尽管这类出生缺陷经常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，但通过家庭和病例对照研究确定易感基因的尝试被证明是不一致的。本研究为研究口腔裂隙的病因和发病机制提供了一种独特的动物模型。纯合子自发突变的小鼠，Dancer，表现出唇裂和腭裂。舞蹈家杂合子小鼠表现出易发生唇裂的倾向：这些突变小鼠在与不同的遗传背景杂交后出现唇裂，它们也表现出显着增加对畸胎原诱导的唇裂的易感性。初步研究已将Dancer突变定位在2.2Mb的基因组区域，该区域与人类染色体区域同线，与裂隙易感性有很强的联系。因此，Dancer突变小鼠提供了一个独特的机会来识别唇裂的易感基因，并表征分子致病过程，包括导致口裂的基因-基因和基因-环境相互作用。针对这一应用提出了两个特定的目标：(1)通过候选基因分析和定位克隆相结合的方法来表征DANCER突变的分子基础；(2)结合微阵列、实时定量PCR、原位杂交和生物信息学分析来表征DANCER突变体中与裂隙发病相关的基因表达谱。这些研究将极大地提高我们对口腔裂隙形成的致病机制的了解，并将导致更好地诊断、治疗和/或预防口面部裂隙的方法的发展。

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.