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我们理解涉及牙列的遗传和获得性疾病的发病机制至关重要。缺牙是最常见的牙齿缺陷。 缺牙，无论是乳牙还是恒牙，都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，并且具有高度的临床相关性。 我们的目标是阐明人类牙齿发育的重要因素，并了解编码这些因素的基因突变如何导致牙齿发育不全。 我们以前已经确定了突变PAX9在一个家庭与缺牙涉及磨牙。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，确定（i）额外的家族，并对这些家族和先前确定的分离病因不明的非综合征性牙发育不全的家族进行采样，以及（ii）潜在牙发育不全的基因。将通过参数和非参数方法进行连锁分析。 候选基因将通过生物信息学和分子方法（包括微阵列方法）进行优先排序。 对选定的候选基因进行突变分析并在家族中进行验证，将确定缺牙基因。 我们的研究将绘制和识别缺牙的基因。这些信息将增加我们对人类牙齿发育的了解，并使我们能够在未来为缺牙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.