GENETIC BASIS OF CLEFT LIP AND PALATE

描述（由申请人提供）：这项拟议研究的长期目标是了解颅面发育和口面裂发病机制的分子遗传机制。口面裂，包括唇裂和腭裂，是常见的出生缺陷，影响全球约1/700的活产。面部裂患者要接受广泛的手术、牙科、语言和心理治疗，通常从婴儿期到青少年期持续多年。尽管与此类出生缺陷相关的频繁发生和广泛昂贵的医学治疗，但导致唇裂和/或腭裂的原因和致病过程尚未得到很好的理解。最近在动物模型系统中的研究表明，面部的发育与其他器官的发育一样，在很大程度上受遗传因素控制。事实上，越来越多的证据表明，特定的基因突变与口面裂有关。我们最近发现，一种名为Twirler的自发突变，导致纯合子突变小鼠唇裂伴腭裂，与Zfhx 1a基因的改变有关。有趣的是，Zfhx 1a基因功能是正常颅面发育所必需的，因为该基因的靶向破坏导致了小鼠的颅面缺陷，包括腭裂。Zfhx 1a基因在进化上是保守的，在人类同源基因中的突变会导致多种发育缺陷。此外，Zfhx 1a基因产物已被证明与BMP和TGF-β信号传导相互作用并调节BMP和TGF-β信号传导，这是调节正常颅面发育的主要分子途径，并参与小鼠和人类的唇腭裂发病机制。因此，我们建议，以确定确切的遗传病变和发展机制的基础面裂形成的Twirler突变小鼠。我们还将确定颅面发育过程中Twirler/Zfhx 1a与BMP/TGF-β信号通路的遗传相互作用。这些研究将大大增加我们对口面裂形成的致病机制的理解，并将导致更好地诊断，治疗和/或预防口面裂的方法的发展。

DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to understand the molecular genetic mechanisms of craniofacial development and of orofacial cleft pathogenesis. Orofacial clefts, including cleft lip and cleft palate, are common birth defects that affect approximately 1 in 700 live births worldwide. Individuals with facial clefts undergo extensive surgical, dental, speech and psychological therapies that usually last for many years from infancy through the teenage years. Despite the frequent occurrence and extensive costly medical treatments associated with such birth defects, the causes and the pathogenic processes that lead to cleft lip and/or cleft palate are not well understood. Recent studies in animal model systems showed that development of the face, like development of other organs, are largely controlled by genetic factors. Indeed, there is accumulating evidence that specific gene mutations are associated with orofacial clefting. We have recently found that a spontaneous mutation, named Twirler, that causes cleft lip with cleft palate in homozygous mutant mice, is associated with alteration of the Zfhx1a gene. Interestingly, the Zfhx1a gene function is required for normal craniofacial development because a targeted disruption in this gene caused craniofacial defects including cleft palate in mice. The Zfhx1a gene is evolutionarily conserved and mutations in the human homolog causes multiple developmental defects. Moreover, the Zfhx1a gene product has been shown to interact with and regulate Bmp and Tgf-beta signaling, major molecular pathways regulating normal craniofacial development and involved in cleft lip/palate pathogenesis in mice and humans. Thus, we propose to determine the exact genetic lesion and the developmental mechanisms underlying facial cleft formation in the Twirler mutant mice. We will also determine the genetic interactions of Twirler/Zfhx1a with the Bmp/Tgf- beta signaling pathways during craniofacial development. These studies will greatly increase our understanding of the pathogenic mechanisms underlying orofacial cleft formation and will lead to development of methods for better diagnosis, treatment and/or prevention of orofacial clefting.