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.
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