MODIFYING GENE DETERMINANTS OF TOOTH AND BONE PHENOTYPES

修改牙齿和骨骼表型的基因决定因素

• 批准号: 6722644
• 负责人: John T. Wright
• 金额: $ 29.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722644
• 关键词: bioinformatics; bone; clinical research; family genetics; gene environment interaction; gene expression; gene interaction; gene mutation; genetic disorder; genotype; hair; human subject; linkage mapping; patient oriented research; phenotype; population genetics; single nucleotide polymorphism; tooth

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.

描述（由申请人提供）：牙-齿-骨综合征（TDO）是一种高度外显的常染色体显性遗传性疾病，影响头发、牙齿和骨骼。我们已经确定了一个4个碱基对缺失的远端3（DLX 3）同源框基因作为这种疾病的分子基础，并表明，所有受影响的个人在多个kinetics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，但它们在TDO的毛发、牙齿和骨骼表现中显示出显著的表型变异性。牙齿大小、骨厚度和骨密度在受影响的个体中是高度可变的。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效应基因引起的。 TDO人群的特殊性质和规模为研究具有相同潜在分子缺陷的人的表型和基因型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识别修饰基因或其他主要影响基因。特定目标1的完成将提供来自因相同DLX 3缺失而分离的家族的受影响和未受影响成员的增加的数量和详细的定量表型表征，并确保鉴定遗传表型修饰物所需的能力。具体目标2是使用两种连锁分析策略鉴定修饰基因或主要效应基因。候选基因方法将用于评价已知在目标组织中对DLX 3重要或与DLX 3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，并将使用该方法来寻找其他重要的修饰基因位点。将对前两个目标的信息进行定量评估，以建立特定目标3中的表型/基因型关系。从这些定量研究中获得的知识将用于进一步关注该人群的表型和基因型研究。 由于基因和环境相互作用的复杂性，通常很难将表型和基因型与被认为是简单的孟德尔性状相关联。这项研究提供了一个独特的机会，通过利用一个特殊的人群，我们目前的人类基因组知识和当前的分子生物学方法的力量，提高我们对表型和基因型的关系和表型的遗传调节的理解。