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

口面部形状的遗传决定因素及其与唇裂/腭裂的关系

• 批准号: 7767390
• 负责人: RICHARD ANDREW SPRITZ
• 金额: $ 60.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767390
• 关键词: Affect; African; Age; Animal Model; Asians; Biological Models; Birth; Candidate Disease Gene; Caucasians; Caucasoid Race; Child; Chromosome Mapping; Cleaved cell; Cleft Lip; Cleft Palate; Comparative Study; Complement; Complex; Congenital Abnormality; DNA; Data; Data Set; Development; Disease; Embryonic Development; Environmental Risk Factor; Ethnic group; Face; Frequencies; Gene Expression; Genes; Genetic; Genetic Determinism; Growth and Development function; Heritability; Hispanics; Human; In Situ Hybridization; Inbred Strains Mice; Latino; Lead; Light; Live Birth; Maps; Measurable; Morphogenesis; Morphology; Mouse Strains; Mus; Normal Range; Not Hispanic or Latino; Pattern; Phenotype; Population; Predisposition; Principal Component Analysis; Principal Investigator; Quantitative Trait Loci; Recombinants; Resources; Role; Sampling; Shapes; Susceptibility Gene; Testing; Variant; base; cleft lip and palate; cohort; craniofacial; gain of function; gene function; genetic analysis; genetic association; genome wide association study; innovation; knock-down; malformation; morphometry; novel strategies; orofacial; population based; public health relevance; research study; response; trait

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.

描述（由申请人提供）：口面部裂，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，在世界各地不同人群中约 1/700 至 1/1000 的活产中发生，约 70% 为散发性、孤立性异常。这种“非综合症”口颌裂具有复杂的特征，涉及多个基因和环境风险因素。迄今为止，传统的基因图谱方法仅确定了非综合征性口颌裂的几个主要易感基因。因此，显然需要新的方法。有大量证据表明，口面部畸形可能发生在中面部尺寸和形状表型变异正常范围的极端情况。在这里，我们提出了一种新方法来识别调节小鼠和人类面部中部形状的基因。我们假设，对正常口面部尺寸和形状起主要作用的基因也将在口面部裂的发生中发挥重要作用。为了识别这些基因，我们将对创新小鼠品系以及选定的人类群体的面部中部形状差异进行详细的形态测量分析，将这些研究与遗传分析相结合，以确定控制面部中部形态测量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遗传差异。我们将利用我们开发的一种宝贵的新资源，即小鼠“协作杂交”(CC)，将 CC 的 8 个创始品系以及精选的重组自交系和重组杂交 (RIX) 之间的面部形状遗传差异与这些小鼠的详细遗传图谱数据关联起来。这种方法将能够识别构成这些形态差异的数量性状基因座（QTL）。我们将通过对人类的类似分析来补充我们的小鼠研究，研究对口颌裂易感性不同的特定人群。这些比较研究将使我们能够识别人类中面部形状的基因。最后，我们将进行功能研究，以评估我们确定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和口面部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面部发育相关的动物模型中的功能研究提供基础。 公共健康相关性：本提案是针对 RFA 的具体回应而提交的，“旨在开发项目，以增进我们对正常颅面发育以及导致疾病和失调的遗传和环境扰动的理解”。该提案将研究小鼠和人类正常口面部发育的遗传决定因素，具体目的是研究这些基因与人类口面部裂隙的关系。