CLONING AND CHARACTERIZATION OF THE VAN DER WOUDE GENE

唇腭裂（CL/P）是一种主要的先天性结构异常，以显著的终身发病率和复杂的病因而闻名。广泛的心理，手术，语言和牙科参与强调了解根本原因的重要性。对于研究者来说，唇腭裂和其他复杂疾病一样，在确定导致其表型的多种遗传，环境和随机因素方面提出了挑战。在这个建议中，我们将通过我们对一种遗传上简单的唇腭裂形式--货车德沃德综合征（VDWS）的研究来探讨唇腭裂的复杂原因。VDWS是唇腭裂最常见的综合征形式，我们认为的形式最适合于促进对更常见的唇腭裂非综合征形式的了解，我们认为的形式最适合于促进对更常见的非综合征形式的了解。本项目的具体目标包括：1）鉴定VDWS基因。致病微缺失的遗传筛选将用于进一步限制包含VDWS基因的区域。强大的基因发现技术，包括整个关键区域的序列分析，将用于识别转录单位。然后，突变筛查将用于发现导致DNA变化的疾病。将进行广泛的突变筛选以搜索功能结构域。2)VDWS基因及其小鼠同源物的表征，包括完整的cDNA和基因组序列分析，时间和组织特异性表达的研究，以确定需要VDWS基因功能的发育途径，并筛选可能在相同途径中发挥功能的基因同源物。3)鉴定调节VDWS基因表达的序列和开发转基因小鼠模型，包括将用于4）长期研究的小鼠敲除，该长期研究将包括互补实验以鉴定途径中的其他基因，并研究环境因素对VDWS基因和相同途径中的其他基因的影响。该项目的影响是，CL/P的研究是有价值的，无论是缺陷本身作为发病率的贡献者的重要性，并为复杂的人类出生缺陷提供了一个模型。VDWS和VDWS样基因的鉴定将立即提供更好的风险咨询，并且它们在环境压力下的表征有望为预防策略和改善治疗做出贡献。此外，VDWS基因的鉴定与CL/P的研究有关，因为它与更常见的非综合征形式的CL/P相似，并且因为它将为颅面发育的最早阶段提供立足点。

Cleft lip and palate (CL/P) is a major congenital structural anomaly that is notable for significant lifelong morbidity and complex etiology.. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. For the investigator, cleft lip and palate, like other complex diseases, provides a challenge in determining the multiple genetic, environmental and stochastic factors that lead to its phenotype. In this proposal, we will pursue the complex causes of cleft lip and palate through our investigations of a genetically simple form of clefting, Van der Woude syndrome (VDWS). VDWS is the most frequent syndromic form of cleft lip and palate and the form we fell is best suited to contribute to an increased understanding of the more common non-syndromic form of cleft lip and palate and the form we feel is best suited to contribute to an increased understanding of the more common non-syndromic form. Specific goals in this project will include: 1) identification of the VDWS gene. A genetic screen for disease-causing micro-deletions will be used to further restrict the region that contains the VDWS gene. Powerful gene-finding techniques, including the sequence analysis of the entire critical region, will be used to identify transcriptional units. Mutation screens will then be used to find disease causing changes in the DNA. Extensive mutation screens will be performed to search for functional domains. 2) characterization of the VDWS gene and its mouse homolog, including complete cDNA and genomic sequence analysis, the study of temporal and tissue-specific expression to identify developmental pathways that require the VDWS gene functional and screens for gene homologs which may function in the same pathway. 3) identification of sequences that regulate VDWS gene expression and the development of transgenic mouse models, including a mouse knockout that will be used in 4) long-term studies that will include complementation experiments to identify other genes in the pathway and investigate the effects of environmental factors on the VDWS gene and other genes in the same pathway. The impact of this project is that studies of CL/P are valuable, both for the importance of the defect itself as a contributor to morbidity and for providing a model for a complex human birth defect. The identification of the VDWS and VDWS-like genes will immediately provide for better risk counseling, and their characterization under environmental stresses hold the promise for contribution to preventative strategies and improved therapeutics. In addition, the identification of the VDWS gene is relevant to studies of CL/P because of its similarities to the more frequent non-syndromic forms of CL/P and because it will provide a foothold into the earliest steps of craniofacial development.