The Genetic Basis of Human Tooth Agenesis

描述（由申请人提供）：Dr. Sylvia A. Frazier-Bowers正在申请一项新的K23指导研究补助金，以发展作为独立的以患者为导向的临床研究者的职业生涯。 这里描述的研究和职业发展计划将联合收割机结合Frazier-Bowers博士在遗传学和遗传学方面的培训，并促进她发展成为一名有能力的颅面复合体人类遗传学研究者。 该提案的目的是发展候选人在先天性缺失牙齿（牙齿发育不全）遗传基础方面进行原创和重要研究的专业知识，这是一个与牙齿矫正学领域非常相关的领域。 尽管最近在人类和小鼠中使用遗传和分子方法取得了进展，但对人类牙齿发育不全的基因知之甚少。 确定牙齿发育不全的分子基础对于研究者理解这种缺陷的发病机制至关重要，并将为改进治疗方式提供基础。 两个基因MSX 1和PAX 9的突变已被确定与非综合征性家族性牙齿发育不全相关。 具体来说，他们实验室的研究发现PAX 9中的插入突变导致磨牙少牙症。 随后，他们又发现了两种导致磨牙少牙的新突变。基于这些研究，他们假设牙齿发育不全是由参与牙齿发育的基因突变引起的，特别是MSX 1和PAX 9。本研究的长期目标是阐明人类牙齿发育不全的遗传病因。目标1将识别，临床表征，并收集样本的个人和/或家庭与多个成员证明 先天缺牙的模式他们将通过不断的筛选工作和横向扩展目前确定的个人的谱系，扩大最近建立的134个个人的数据库。将从这些家庭收集的血液或口腔细胞样本中收集DNA。目的2：通过对28例磨牙缺失患者的MSX 1和PAX 9基因进行测序，确定与磨牙缺失相关的MSX 1和PAX 9基因突变。这些研究将有助于确定这两个基因是否是大多数磨牙缺牙病例的原因，或者其他关键候选基因如LEF 1或BMP 4是否在某些情况下负责。目的3将利用全基因组筛选确定导致非综合征型下颌切牙发育不全的基因的染色体定位。目的4在目的3中确定的染色体区域中筛选候选基因，以确定下颌切牙发育不全的病因。因此，确定这里提出的牙齿发育不全的特定模式的遗传基础对于获得性和遗传性牙齿缺失的可能治疗具有重要意义。这项研究是申请人的职业目标的核心，这是执行独立和原创的研究，是相关的识别导致正畸问题的遗传因素。

DESCRIPTION (provided by applicant): Dr. Sylvia A. Frazier-Bowers is applying for a new K23 mentored research grant to develop a career as an independent patient-oriented clinical investigator. The research and career development plans described here will combine Dr. Frazier-Bowers' training in orthodontics and genetics and facilitate her development into a competent investigator of the human genetics of the craniofacial complex. The objectives of this proposal are to develop the candidate's expertise in conducting original and significant research of the genetic basis of congenitally missing teeth (tooth agenesis), an area of great relevance to the field of orthodontics. Despite recent advances using genetic and molecular approaches in humans and mice, little is known about the genes involved in human tooth agenesis. Determining the molecular basis for tooth agenesis is critical to the investigator's understanding of the pathogenesis of this defect, and will provide the basis for improved treatment modalities. Mutations in two genes, MSX1 and PAX9, have been identified in association with non-syndromic familial tooth agenesis. Specifically, studies in their laboratory led to the discovery that an insertion mutation in PAX9 causes molar oligodontia. They have subsequently identified two more novel mutations responsible for molar oligodontia. Based on these studies, they hypothesize that tooth agenesis arises from mutations in genes involved in tooth development, particularly MSX1 and PAX9. The long-term goals of this research are to elucidate the genetic etiology of human tooth agenesis. Aim 1 will identify, clinically characterize, and collect samples from individuals and/or families with multiple members demonstrating patterns of congenitally missing teeth. They will expand their recently established database of 134 individuals through continual screening efforts and by laterally extending the pedigrees of individuals currently identified. DNA will be harvested from blood or buccal cell samples collected from these families. Aim 2 proposes to use the collected samples to identify MSX1 and PAX9 mutations associated with molar oligodontia by sequencing these genes in 28 patients affected with molar oligodontia. These studies will help to determine if these two genes are responsible for the majority of cases of molar oligodontia, or if other key candidate genes such as LEF1, or BMP4 are responsible in some cases. Aim 3 will utilize a genome-wide screen to determine the chromosomal location of the gene causing non-syndromic mandibular incisor agenesis. Aim 4 proposes to screen candidate genes in the chromosomal region identified in Aim 3 to determine the cause of mandibular incisor agenesis. Thus, determining the genetic basis of specific patterns of tooth agenesis as proposed here has significant implications for the possible treatment of both acquired and inherited loss of teeth. This research is central to the career goals of the applicant, which are to perform independent and original research that is relevant to identifying genetic factors that lead to orthodontic problems.