MOLECULAR GENETICS OF HYPODONTIA

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Hypodontia is defined as the hereditary absence of between one and four permanent teeth. Tooth morphogenesis relies upon reciprocal interactions between epithelial and mesenchymal cells. Homeotic genes that regulate Drosophila melangaster development were recently shown to be expressed during inductive epithelial-mesenchymal interactions associated with tooth and limb morphogenesis. Mutations or transgenic knockouts of homeotic genes, transcription factors or their downstream targets have led to blocked tooth development. Our hypothesis is that hypodontia is a common phenotype resulting from mutations in different genes controlling the development of teeth. We have identified a new and unusual bilateral maxillary cuspid hypodontia pedigree for study. Specific Aims are: I) to assemble reasonable candidate gene markers and carry out linkage analyses using appropriate microsatellite markers, leading to inclusion of a locus or exclusion of a locus not linked to this hypodontia phenotype. If successful, we intend to sequence the affected candidate gene to determine the nature of the mutation. ii) the candidate gene approach is uninformative, we will begin a genome-wide random mapping search for the hypodontia gene. We predict that similar studies on a number of distinct forms of hypodontia will lead to identification of the early steps in pathways controlling tooth and limb development.