Tricho-dento-osseous syndrome (TDO) is an autosomal dominant hereditary disorder that primarily affects hair, teeth and bone. The TDO phenotype is variable in severity and distribution of affected tissues. This clinical variability has resulted in the subclassification of TDO into three types, yet it is unclear if these are the result of variable expression of a single common gene mutation, allelic or nonallelic mutations. The genetic etiology of TDO is unknown. Recently the Investigators have identified genetic linkage for TDO within a 20cM region of chromosome 17 in four North Carolina families. The goal of this proposal is to identify the TDO related gene and to characterize the clinical phenotype in seven kindreds. Six large multiplex families in North Carolina and one Virginia family segregating for TDO have been identified for investigation. Four generations of affected and unaffected individuals are available from each kindred and live geographically close to the investigators making this an ideal population for gene mapping studies. A minimum of 85 affected and 85 unaffected people will be used for clinical characterization and genetic studies. Thorough clinical and radiographic examinations will be performed to identify affected individuals and to characterize the clinical features of TDO in these families. The investigators propose three broad strategies to permit identification of the TDO causing gene: 1) Refinement of the genetic candidate region through continued linkage and haplotype studies, 2) Resolution of the genetic and physical maps of the candidate region to definitively include/exclude genes/ESTs as candidates for TDO, and 3) Mutational analysis of the TDO candidate genes/ESTs. Establishing the molecular basis of TDO is essential to understanding the pathogenesis of this disorder. The presence of defects in both ectodermal and mesenchymal tissues in TDO suggests that essential and shared processes of tissue formation exist and are dysfunctional. Anomalies of these tissues are common to many craniofacial genetic syndromes. In addition to enhancing the diagnosis and treatment of TDO patients, the broader implications of this research lie in advancing our understanding of the basic developmental controls involved in the formation of hair, teeth and bone.
