Genetic Characterization of a Novel Model of Cleft Palate

描述(申请人提供)：口腔裂伤是人类最常见的出生缺陷之一，大约每700名活产儿中就有1人受到影响。这种频率可能源于颅面形态发生的复杂性，这需要对基因表达变化、细胞生理变化和形态发生运动进行精确调控。虽然越来越多的基因被认为与唇裂和腭裂有关，但控制口腔面部畸形的机制仍不清楚。这个项目的总体目标是通过使用一种新的腭裂小鼠模型来扩大我们对口面部裂隙遗传基础的理解。ENU诱导的clfp4小鼠存在隐性突变，导致继发性腭裂、脐膨出和高外显性骨骼畸形。虽然在人类综合征中观察到同时出现口面部劈裂和体壁缺陷，但很少有小鼠模型概括这些表型。初步的图谱数据将突变放在10号染色体的远端，这一区域的这种表型组合还没有报道。因此，clfp4可能代表了一种新的头面部/体壁出生缺陷模型。虽然初步的表型分析表明，该突变体中的腭裂是由于腭架抬高失败造成的，但通过鉴定clfp4致病基因，将极大地促进更详细的实验的有效设计和解释，如标记分析。为了发展这一独特的腭裂模型，并阐明其表型的机制，我们建议通过高分辨率的遗传作图和有针对性的重新测序来确定cflp4突变背后的基因，并进行基本的表型分析，以开始了解该缺陷的机制基础。这项工作将提高我们对调节腭裂发生的分子网络的理解，为开发新的诊断、预防和治疗腭裂和其他颅面疾病的方法提供基础。 与公共卫生相关：口面部裂是人类最常见的出生缺陷之一，每700名活产儿中就有一名受到影响。手术修复和术后治疗的总保健费用令人震惊，这种疾病的毁容往往会对受影响的个人造成毁灭性的社会和心理后果。这一建议将扩大我们对使用新型小鼠腭裂和颅面畸形模型的口面部裂伤病因的理解，为开发诊断、预防和治疗腭裂和其他颅面畸形的新方法奠定基础。

DESCRIPTION (provided by applicant): Orofacial clefting is one of the most common birth defects in humans, affecting approximately 1 in 700 live births. This frequency likely stems from the complexity of craniofacial morphogenesis, which requires precise regulation of gene expression changes, alterations in cell physiology and morphogenic movements. Although an increasing number of genes have been linked to cleft lip and cleft palate, the mechanisms governing orofacial malformations remain unclear. The overall objective of this project is to expand our understanding of the genetic basis of orofacial clefting through the use of a novel mouse model of cleft palate. The ENU-induced clfp4 mouse harbors a recessive mutation causing cleft secondary palate, omphalocele and skeletal malformations with high penetrance. While simultaneous presentation of orofacial clefting and body wall defects is observed in human syndromes, there are few mouse models that recapitulate these phenotypes. Preliminary mapping data places the mutation at the distal end of Chromosome 10, a region where this combination of phenotypes has not been reported. Thus, clfp4 likely represents a new model of craniofacial/body wall birth defects. Although preliminary phenotypic analysis has revealed that cleft palate in this mutant results from a failure of palate shelf elevation, efficient design and interpretation of more detailed experiments, such as marker analysis, would be greatly facilitated by identification of the clfp4 causative gene. To develop this unique model of cleft palate and to elucidate the mechanism underlying the phenotype, we propose to identify the gene that underlies the cflp4 mutation through high-resolution genetic mapping and targeted re-sequencing, and perform basic phenotypic analysis to begin to understand the mechanistic basis of the defect. This work will improve our understanding of the molecular networks that regulate palatogenesis, providing a foundation for the development of new methods for the diagnosis, prevention and treatment of cleft palate and other craniofacial disorders. PUBLIC HEALTH RELEVANCE: Orofacial clefting is one of the most common birth defects in humans, affecting 1 in 700 live births. The total health care costs for surgical repair and post-operative therapies is staggering, and the disfigurement of such disorders often have devastating social and psychological consequences for the affected individual. This proposal will expand our understanding of the etiology of orofacial clefting using a novel mouse model of cleft palate and craniofacial malformations, providing a foundation for the development of new methods for the diagnosis, prevention and treatment of cleft palate and other craniofacial disorders.