MODIFYING GENE DETERMINANTS OF TOOTH AND BONE PHENOTYPES

描述（由申请人提供）：毛牙骨综合征（TDO）是一种高渗透性常染色体显性遗传疾病，影响头发、牙齿和骨骼。我们在无远端3 （DLX3）同源盒基因中发现了一个4个碱基对的缺失作为这种疾病的分子基础，并表明在多个种类中所有受影响的个体都具有相同的缺失。尽管受影响的个体具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着的表型变异。牙齿大小，骨厚度和骨密度在受影响的个体中变化很大。我们假设这种主要TDO特征的表型变异性是由修饰基因或其他主要作用基因引起的。

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.