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我们理解涉及牙列的遗传和获得性疾病的发病机制和治疗至关重要。在这些异常中，牙齿缺失（下颌缺损）是牙医遇到的最常见的缺陷。由于先天性缺失或在成年生活中缺失恒牙是一个重要的公共卫生问题，具有高度的临床相关性。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人类牙齿发育的重要因素，并在体外和体内模型系统中解剖它们的生物学。在这里，我们建议鉴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收集所有可用成员的血液样本来实现这一目标，这些成员分离出一种独特的下颌畸形。在接受评估的58名家庭成员中，有22人至少缺失了一颗完整的臼齿，平均至少缺失了两对臼齿。基因组扫描将对来自下颌畸形亲属的基因组DNA进行高度多态性微卫星标记，以确定下颌畸形位点的染色体位置。为了识别下颌畸形基因，将从所有已知基因和候选区间内的表达序列标签（est）中选择“强”候选基因。后者将通过化学裂解和直接DNA测序进行突变分析。我们还将共同努力，通过扩大家族，识别匿名STSs映射到该区域的cdna，并系统地进行突变分析，来完善候选区间。这些努力预计将使我们能够识别人类新下颌位点的基因，并将在未来使我们能够研究其生物学及其与其他已知因素的相互作用，这些因素对牙齿发育很重要。

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.