Cloning and characterization of the Van Der Woude gene

唇腭裂是一种常见的先天性畸形，终生发病率高。的广泛 心理、手术、言语和牙科的参与强调了理解 根本原因我们的长期目标是发现基因和环境因素， 这种混乱。然而，唇腭裂的病因是复杂的，并鉴于大量的基因 据预测，与孤立的唇腭裂有关，基因发现构成了一个重大挑战。的 本研究将采用一种简单的口面裂遗传模型--货车德沃德综合征。 货车der Woude综合征是孤立性唇腭裂的一个杰出的临床模型， 区别特征是下唇有凹陷。干扰素调节因子6（IRF 6）的突变导致货车der 伍德综合征。此外，IRF 6的遗传变异赋予了孤立性唇腭裂的风险，表明 货车德沃德综合征也是一个杰出的遗传模型。因此，IRF 6对于关键的 在腭发育的途径，它的发现代表了在这一途径的立足点。这个的主要目标 一个建议是通过首先确定IRF 6的体内功能，然后鉴定IRF 6的活性， 调节IRF 6表达的因子。本文的目的有三：1）为货车der建立小鼠模型 Woude综合征的发病机制进行了全面的分析。 这些小鼠的腭发育。研究I型干扰素在小鼠腭发育中的作用， IRF 6是转录因子的干扰素调节家族的成员。2)为了评估一个潜在的基因 Irf 6和转化生长因子0，3（TgfliS）突变之间的相互作用，因为TgfliJ 3是必需的 腭发育和腭中Irf 6的表达。作为Irf 6和Irf 6的双杂合子的小鼠 将分析TgflJS的腭发育。此外，为了检查Irf 6在转导细胞中的潜在作用， 腭发育过程中的TgfliS信号。3)为了鉴定调控腭部Irf 6表达的增强子， 使用转基因小鼠。TgffJS通过SMADs或其他转录因子或两者来调节Irf 6吗？ 这些目标的完成将促进我们对IRF 6在腭发育中的作用的理解，并确定 新的基因相互作用和基因，可能有助于孤立的唇腭裂，一种常见的人类疾病。 这些知识将为加强诊断测试和未来的预防性干预措施提供基础。

Cleft lip and palate is a common congenital anomaly with significant lifelong morbidity. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. Our long-term objective is to discover the genes and environmental factors that contribute to this disorder. However, the etiology of cleft lip and palate is complex, and given the large number of genes predicted to be involved in isolated cleft lip and palate, gene discovery poses a significant challenge. The approach used here will be to study a genetically simple model of orofacial clefting, Van der Woude syndrome. Van der Woude syndrome is an outstanding clinical model for isolated cleft lip and palate, as its only distinguishing features are pits in the lower lip.Mutations in Interferon Regulatory Factor 6 (IRF6) cause Van der Woude syndrome. Moreover, genetic variation in IRF6 confers risk for isolated cleft lip and palate, demonstrating that Van der Woude syndrome is also an outstanding genetic model. Thus, IRF6 is essential for a critical pathway in palate development, and its discovery represents a foothold in this pathway. The main goal of this proposal is to delineate the IRF6 pathway by first determining the in vivo function of IRF6 and then identifying factors that regulate the expression of IRF6. There are 3 Aims: 1) To generate a mouse model for Van der Woude syndrome by mutating Irf6, and to perform a comprehensive analysis of the pathogenic processes in palate development in these mice. To investigate a role for Type I interferons in palate development in mice, as IRF6 is a member of the Interferon Regulatory family of transcription factors. 2) To evaluate a potential genetic interaction between mutations in Irf6 and Transformation growth factor 0,3 (TgfliS), since TgflJ3 is necessary for palate development and for Irf6 expression in the palate. Mice that are double heterozygotes for Irf6 and TgflJS will be analyzed for palate development. Also, to examine the potential role for Irf6 in transducing the TgfliS signal during palate development. 3) To identify the enhancer that regulates Irf6 expression in the palate using transgenic mice. Does TgffJS regulate Irf6 through the SMADs or by other transcription factors or both? Completion of these aims will advanceour understanding for the role of IRF6 in palate development, and identify novel gene interactions and genes that may contribute to isolated cleft lip and palate, a common human disorder. This knowledge will provide the basis for enhanced diagnostic tests and future preventive interventions.