Cloning and characterization of the Van Der Woude gene

唇腭裂是一种常见的先天性畸形，具有显著的终生发病率。广博的 心理、外科、言语和牙科介入强调了解 根本原因。我们的长期目标是发现影响人类健康的基因和环境因素 这种紊乱。然而，唇腭裂的病因是复杂的，并且考虑到大量的基因 预计将与孤立的唇腭裂有关，基因发现构成了一个重大挑战。这个 这里使用的方法是研究一种简单的口裂遗传模型--范德伍德综合征。 范德伍德综合征是治疗孤立性唇腭裂的一种优秀的临床模型。 明显的特征是下嘴唇上的凹坑。干扰素调节因子6(IRF6)的突变导致范德 武德综合征。此外，IRF6的遗传变异增加了孤立性唇腭裂的风险，表明 范德伍德综合征也是一种杰出的遗传模式。因此，IRF6对于一个关键的 它的发现代表了这一途径的一个立足点。这样做的主要目标是 建议首先确定IRF6在体内的功能，然后鉴定IRF6途径 调节IRF6表达的因子。有三个目标：1)为Van Der建立一个小鼠模型 Woude综合征，并对其致病过程进行全面分析。 这些小鼠的味觉发育。目的：探讨I型干扰素在小鼠腭部发育中的作用。 IRF6是干扰素调节转录因子家族的成员。2)评估潜在的遗传 IRF6突变与转化生长因子0，3(TgfliS)的相互作用，因为TgflJ3是必需的 对于上颚发育和上颚中IRF6的表达。IRF6和IRF6双重杂合子的小鼠 将对TgflJS进行分析，以了解上颌发育情况。此外，为了研究IRF6在转导细胞中的潜在作用 TgfliS信号在上颚发育过程中。3)确定在腭部调节irf6表达的增强子 使用转基因小鼠。TgffJS是通过Smads还是通过其他转录因子调控IRF6，还是两者兼而有之？ 这些目标的完成将促进我们对IRF6在味觉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导致孤立的唇腭裂，这是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干预提供基础。

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.