THE GENOTYPE AND PHENOTYPE AMELOGENESIS IMPERFECTA

釉质发生不全是一组主要影响牙齿釉质形成的遗传性疾病。这些疾病的分子基础是异质性的，常染色体显性遗传、常染色体隐性遗传和X连锁遗传已被记录在案。这项建议的直接目标是确定与常染色体显性AI相关的基因/S，并表征相关的牙齿表型及其变异性。已经确定了多个大家庭，这些家庭有四代受影响和未受影响的个体分离为常染色体显性AI。至少140名受影响的人和140名未受影响的人将被用于基因分析和表型表征。标准化的X线片将被用来描述和量化颅面复合体的特征，并评估牙齿受累情况。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。基因分型将使用连锁分析来确定候选基因座，评估已知的候选基因座，如有必要，还将采用全基因组搜索方法。首先将测试与可能的候选基因座之间的联系。AI基因将通过对具有跨越候选区域的高密度遗传标记的家庭成员进行基因分型来进行亚本地化。候选基因将使用SSCP(单链构象多态分析)、异源双链突变分析和DNA直接测序进行检测。然后，将评估候选基因的突变在受影响和未受影响的家庭成员中的分离情况。本研究的近期目标是研究常染色体显性遗传性AI家系的AI表型和表型变异，提炼AI特征的基因组座位，并确定相关基因和基因突变(S)。对AI表型的了解将立即对这些具有显著口腔发病率的疾病的诊断和治疗有用。这项研究还将提供有关牙釉质形成的分子控制的基本信息。了解形态发生和组织形成的分子决定因素将使新的、更有效的治疗方法和对影响牙齿的各种遗传条件的更准确诊断成为可能。

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.