GENETIC BASIS OF AUTOSOMAL DOMINANT HYPODONTIA

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和治疗至关重要。在这些畸形中，缺牙(缺牙)是牙医遇到的最常见的缺陷。由于成人先天缺失或缺失而导致的恒牙缺失是一个重要的公共卫生问题，具有很高的临床意义。人们对人类牙齿缺失的遗传基础知之甚少。我们的长期目标是阐明对人类牙齿发育至关重要的因素，并在体外和体内模型系统中剖析它们的生物学。在这里，我们建议确定一个对人类牙齿发育重要的基因。我们将通过临床评估和采集所有可用的大家族成员的血液样本来实现这一点，分离出一种独特的缺牙症。在接受评估的58名家庭成员中，有22名成员至少缺少一套完整的磨牙，平均而言，至少缺少两对磨牙。将利用基因组DNA上高度多态的微卫星标记进行基因组扫描，以确定下牙基因座的染色体位置。为了识别缺牙基因，将从所有已知的基因和候选区间内映射的表达序列标签(EST)中选择“强”候选基因。将通过化学切割和DNA直接测序对后者进行突变分析。我们还将共同努力，通过扩大家族，确定用于匿名STSS映射到该区域的cDNA，并系统地进行突变分析，来细化候选区间。这些努力有望让我们识别人类一个新的缺牙基因座的基因，并在未来允许我们研究它的生物学，并与其他已知的对牙齿发育重要的因素相互作用。

Elucidating the genetic control of morphogenesis and cell differentiation during tooth development is crucial to our understanding of the pathogenesis and treatment of genetic and acquired diseases that involve dentition. Of these anomalies, missing teeth (hypodontia) constitutes the most common defect encountered by dentists. The lack of permanent teeth due to congenital absence or loss in adult life is an important public health concern of high clinical relevance. Little is known about the genetic basis of missing teeth in humans. Our long term goal is to elucidate factors important for tooth development in humans and to dissect their biology in in vitro and in vivo model systems. Here we propose to identity a gene important for tooth development in humans. We will accomplish this by clinically evaluating and collecting blood samples from all available members of a large kindred segregating a unique form of hypodontia. Twenty two of 58 members of the family evaluated are missing at least one complete set of molars and on average, at least two pairs of molars. A genome scan will be conducted with highly polymorphic microsatellite markers on genomic DNA from members of the hypodontia kindred in order to determine the chromosomal location of the hypodontia locus. To identity the hypodontia gene, "strong" candidates will be selected from all known genes and expressed sequence tags (ESTs) that map within the candidate interval. Mutation analysis will be conducted on the latter by chemical cleavage and direct DNA sequencing. We will also make a concerted effort to refine the candidate interval by expanding the family, and identifying cDNAs for anonymous STSs mapping to the region and systematically conducting mutation analysis. These efforts are expected to allow us to identity a gene for a new hypodontia locus in humans, and will in the future, allow us to study its biology and interplay with other known factors important for tooth development.