MODIFYING GENE DETERMINANTS OF TOOTH AND BONE PHENOTYPES

描述(申请人提供)：毛发-齿状骨综合征(TDO)是一种高度渗透性的常染色体显性遗传性疾病，影响头发、牙齿和骨骼。我们已经确定远端缺失3(DLX3)同源框基因中的四个碱基对缺失是这种疾病的分子基础，并表明在多个家系中所有受影响的个体都有相同的缺失。尽管受影响的个体有相同的四个碱基对缺失，但他们在TDO的头发、牙齿和骨骼表现上表现出显著的表型变异。牙齿大小、骨厚度和骨密度在受影响的个体中差异很大。我们假设，主要TDO特征的这种表型变异是由修饰基因或其他主效基因造成的。 TDO群体的特殊性质和大小为研究具有相同潜在分子缺陷的人的表型和基因之间的关系提供了独特的机会。我们建议通过完成三个特定的目标来确定修饰基因或其他主要影响基因。具体目标1的完成将提供来自分离相同DLX3缺失的家庭的受影响成员和未受影响成员的数量增加和详细的定量表型特征，并确保识别遗传表型修饰物所需的能力。具体目标2旨在利用两种连锁分析策略识别修饰基因或主效基因。候选基因方法将用于评估已知的在感兴趣组织中重要的或与DLX3共表达的基因。我们已经证明了全基因组扫描方法的可行性，并将使用该方法来搜索其他重要的修饰基因位点。来自前两个目标的信息将被定量评估，以建立特定目标的表型/基因关系3。从这些定量研究中获得的知识将被用来进一步关注这一群体的表型和基因研究。 由于基因和环境相互作用的复杂性，通常很难将被认为是简单孟德尔特征的表型和基因型联系起来。这项研究提供了一个独特的机会，通过利用一个特殊的人类群体、我们对人类基因组的现有知识和现有分子生物学方法的力量，来促进我们对表型和基因型的关系以及表型的遗传调控的理解。

DESCRIPTION (provided by applicant): The tricho-dento-osseous syndrome (TDO) is a highly penetrant autosomal dominant hereditary disorder that affects hair, teeth and bone. We have identified a four base pair deletion in the distal-less 3 (DLX3) homeobox gene as the molecular basis of this disorder and shown that all affected individuals in multiple kindreds have the same deletion. Despite affected individuals having the same four base pair deletion they show marked phenotypic variability in the hair, teeth and bone manifestations of TDO. Tooth size, bone thickness and bone density are highly variable in affected individuals. We hypothesize that this phenotypic variability of the major TDO features results from modifying genes or other genes of major effect. The special nature and size of the TDO population provides a unique opportunity to study the relationship between phenotype and genotype in people with the identical underlying molecular defect. We propose to identify modifying genes or other genes of major effect by the completion of three specific aims. Completion of specific aim 1 will provide increased numbers and detailed quantitative phenotype characterization of affected and unaffected members from families segregating for the same DLX3 deletion and ensure the power necessary to identify genetic phenotypic modifiers. Specific aim 2 is directed at identifying modifying genes or genes of major effect using two linkage analysis strategies. A candidate gene approach will be used to evaluate genes known to be important in or co-expressed with DLX3 in the tissues of interest. We have shown the feasibility of and will use a genome wide scan approach to search for additional important modifying gene loci. Information from the first two aims will be quantitatively evaluated to establish phenotype/genotype relationships in specific aim 3. Knowledge from these quantitative studies will be used to further focus both the phenotype and genotype studies of this population. Because of complexities in gene and environmental interactions it is typically difficult to correlate phenotype and genotype for what are considered simple Mendelian traits. This study provides a unique opportunity to advance our understanding of the relationship of phenotype and genotype and the genetic modulation of phenotype by taking advantage of a special human population, our current knowledge of the human genome and the power of current molecular biological approaches.