Genetic Determinants of Orofacial Shape and Relationship to Cleft Lip/Palate

描述(申请人提供)：口腔颌面裂，主要是唇裂(CL)、腭裂(CP)和唇腭裂(CLP)，是最常见的主要出生缺陷之一，在世界各地的不同人口中发生在约1/700至1/1000的活产儿中，约70%是零星的、孤立的异常。这种“非综合征性”的口裂表现为复杂的特征，涉及多个基因和环境风险因素。到目前为止，传统的遗传作图方法只确定了几个非综合征性口面部裂的主要易感基因。因此，显然需要新的方法。有相当多的证据表明，在面部中部大小和形状的表型变异的正常范围内，口腔面部畸形可能会发生。在这里，我们提出了一种新的方法来识别在老鼠和人类中调控面中部形状的基因。我们假设，决定正常口腔面部大小和形状的基因也将在口腔裂隙的发生中发挥重要作用。为了识别这些基因，我们将对创新的小鼠品系以及选定的人类群体中的面中部形状差异进行详细的形态计量分析，将这些研究与遗传分析相结合，以确定控制面中部形态测量的主要决定因素的基因。我们的研究表明，特定近交系小鼠在面部形状的可测量参数方面存在可遗传差异。我们将利用我们开发的一种有价值的新资源--小鼠“协作杂交”(CC)，将CC的8个创始品系之间在面部形状上的可遗传差异与精选的重组近交系和重组杂交(Rix)相关联，并提供这些小鼠的详细遗传图谱数据。这种方法将使数量性状基因座(QTL)的识别成为可能，这些QTL是这些形态测量学差异的基础。我们将用对人类的类似分析来补充我们的老鼠研究，研究对口面部裂有不同易感性的特定人群。这些比较研究将使我们能够识别构成人类面部中部形状的基因。最后，我们将进行功能研究，以评估我们识别的基因如何影响面部形状。总之，这些研究应该为理解人类面部形态发生与口裂易感性之间的关系提供基础，并为启动这些基因在与人类口腔面部发育相关的动物模型中的功能研究提供基础。 与公共健康相关：这项提案是针对RFA提出的，旨在开发项目，以促进我们对导致疾病和紊乱的基因和环境扰动的正常头面部发育的了解。这项建议将研究小鼠和人类正常口腔面部发育的遗传决定因素，具体目的是调查这些基因与人类口腔裂隙的关系。

DESCRIPTION (provided by applicant): Orofacial clefts, principally cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), are among the most common major birth defects, occurring in ~1/700 to 1/1000 live births in various populations around the world, ~70% as a sporadic, isolated abnormality. Such "non-syndromic" orofacial clefts act as complex traits, involving multiple genes and environmental risk factors. To date traditional genetic mapping approaches have identified only a few major susceptibility genes for non-syndromic orofacial clefts with certainty. Therefore, new approaches are clearly required. There is considerable evidence that orofacial malformations can occur at the extremes of the normal ranges of phenotypic variation of midfacial size and shape. Here we propose a novel approach to identify genes that regulate midfacial shape in mouse and human. We hypothesize that genes that are major contributors to normal orofacial size and shape will also have important roles in the occurrence of orofacial clefts. To identify such genes, we will perform detailed morphometric analysis of midfacial shape differences in innovative mouse strains as well as in select human populations, combining these studies with genetic analyses to identify genes that control major determinants of midfacial morphometries. Our studies have shown that specific inbred strains of mice have heritable differences in measurable parameters of facial shape. We will take advantage of a valuable new resource we have developed, the mouse "Collaborative Cross" (CC), to correlate heritable differences in facial shape among the 8 founder strains of the CC, along with select Recombinant Inbred lines and Recombinant Intercross (RIX), with detailed genetic mapping data for these mice. This approach will enable identification of quantitative trait loci (QTLs) that underlie these morphometric differences. We will complement our mouse studies with a similar analysis of humans, studying specific populations with different susceptibilities to orofacial clefts. These comparative studies will allow us to identify genes that underlie midfacial shape in humans. Finally, we will perform functional studies to assess how the genes we have identified can influence facial shape. Together, these studies should provide a basis for understanding the relationship between human facial morphogenesis and susceptibility to orofacial clefts, and for initiating studies of the functions of these genes in animal models relevant to human orofacial development. PUBLIC HEALTH RELEVANCE: This proposal is submitted in specific response to an RFA "to develop projects to advance our understanding of normal craniofacial development and the genetic and environmental perturbations that lead to diseases and disorders." This proposal will study the genetic determinants of normal orofacial development in mouse and human, with the specific intent of investigating relationship of these genes to human orofacial clefts.