MOLECULAR GENETICS OF HUMAN TOOTH DEVELOPMENT

阐明牙齿发育过程中形态发生和细胞分化的遗传控制对于我们理解涉及牙列的遗传性和获得性疾病的发病机制至关重要。缺牙是最常见的牙体缺损症。缺少乳牙或恒牙是一个重要的公共卫生问题，容易导致营养不良和继发性感染，具有很高的临床相关性。 我们的目标是阐明对人类牙齿发育至关重要的因素，并了解编码这些因素的基因突变如何导致牙齿发育不足。我们之前已经在一个涉及磨牙的缺牙家庭中发现了PAX9的突变。我们建议通过全基因组连锁分析、候选基因鉴定和突变分析来确定(I)额外的家系，并对这些家系和以前发现的分离原因不明的非综合征性缺牙的家系进行采样，以及(Ii)导致缺牙的基因(S)。联动分析将通过参数和非参数方法进行。候选基因将被生物信息学和包括微阵列方法在内的分子方法优先考虑。对选定的候选基因进行突变分析，并在家系中进行验证，将确定缺牙基因(S)。我们的研究将绘制并识别导致牙齿减少的基因。这些信息将增加我们对人类牙齿发育的了解，并使我们能够为未来的牙齿缺乏症患者设计更好的诊断和治疗策略。

Elucidating the genetic control of morphogenesis and cell differentiation during tooth development is crucial to our understanding of the pathogenesis of genetic and acquired diseases that involve dentition. Hypodontia constitutes the most commonly encountered dental defect. The lack of teeth, primary or permanent, is an important public health concern predisposing to malnutrition and secondary infections, and is of high clinical relevance. Our goal is to elucidate factors important for tooth development in humans and to understand how mutations within genes encoding these factors contribute to hypodontia. We have previously identified a mutation in PAX9 in a family with hypodontia involving molars. We propose to identify (i) additional families and sample these and previously identified families segregating non-syndromic hypodontia of unknown etiology and (ii) the gene(s) underlying hypodontia by genome-wide linkage analysis, candidate gene identification and mutation analysis. Linkage analysis will be conducted by parametric and non-parametric approaches. Candidate genes will be prioritized by bioinformatics and molecular approaches including a microarray approach. Mutation analysis of selected candidate genes and validation in families will identify the hypodontia gene(s). Our studies will map and identify genes underlying hypodontia. This information will add to our knowledge of human tooth development and enable design of better diagnostic and treatment strategies for hypodontia patients in the future.