THE GENOTYPE AND PHENOTYPE AMELOGENESIS IMPERFECTA

无釉质发育不全症（AI）是一组主要影响牙齿牙釉质形成的遗传性疾病。这些疾病的分子基础是异质的，常染色体显性遗传，常染色体隐性遗传和x连锁遗传已被证实。本建议的直接目标是确定与常染色体显性AI相关的基因，并表征相关的牙齿表型及其变异性。多个大家庭四代受影响和未受影响的个体分离为常染色体显性AI已确定进行调查。至少140名受影响和140名未受影响的人将用于基因型分析和表型表征。标准化的x线片将用于描述和量化颅面复合体的特征，并评估牙齿的受累情况。将使用分层方法来识别每个家庭中与AI相关的AI分子缺陷。基因分型将通过连锁分析来确定候选基因座，评估已知的候选基因座，并在必要时采用全基因组搜索方法。将首先检测与假定候选基因座的连锁。人工智能基因将通过对跨越候选区域的高密度遗传标记进行基因分型的家庭成员进行亚定位。候选基因将使用SSCP（单链构象多态性分析）、异双工突变分析和直接DNA测序进行测试。然后将评估候选基因的突变，以便在受影响和未受影响的家庭成员中进行分离。本研究的直接目标是表征常染色体显性AI家庭的AI表型和表型变异性，完善AI性状的基因组位点，并确定相关基因和基因突变。对AI表型的了解将对这些具有显著口腔发病率的疾病的诊断和治疗立即有用。本研究也将为牙釉质形成的分子调控提供基础信息。形态发生和组织形成的分子决定因素的知识将允许新的和更有效的治疗和更准确的诊断影响牙齿的各种遗传条件。

Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect primarily the enamel formation of teeth. The molecular basis of these disorders is heterogeneous with autosomal dominant, autosomal recessive and X-linked inheritance having been documented. The immediate goal of this proposal is to identify the gene/s associated with autosomal dominant AI and characterize the associated dental phenotype and its variability. Multiple large families with four generations of affected and unaffected individuals segregating for autosomal dominant AI have been identified for investigation. A minimum of 140 affected and 140 unaffected people will be used for genotype analysis and phenotype characterization. Standardized radiographs will be used to characterize and quantify features of the craniofacial complex and evaluate dental involvement. A hierarchical approach will be used to identify the AI associated AI molecular defect in each family. Genotyping will be accomplished using linkage analysis to identify candidate loci evaluating known candidate gene loci and if necessary a genome wide search approach. Linkage to putative candidate loci will be tested first. AI genes will be sub-localized by genotyping family members with high density genetic markers that span the candidate region. Candidate genes will be tested using SSCP (Single Strand Conformational Polymorphism Analysis), heteroduplex mutational analysis and direct DNA sequencing. Mutations in candidate genes will then be evaluated for segregation in the affected and unaffected family members. The immediate goals of this research are to characterize the AI phenotype and phenotypic variability in families with autosomal dominant AI, to refined the genomic loci for the AI traits, and to identify the associated genes and gene mutation(s). Knowledge of the AI phenotype will be immediately useful in the diagnosis and treatment of these disorders that have significant oral morbidity. This investigation also will provide basic information regarding the molecular control of enamel formation. Knowledge of the molecular determinants of morphogenesis and tissue formation will allow novel and more effective treatments and more accurate diagnosis of the diverse hereditary conditions affecting teeth.