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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012202-02
Application #
2882729
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Sharrock, William J
Project Start
1998-03-01
Project End
2001-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Dentistry
Type
Schools of Dentistry
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Wright, J Timothy; Torain, Melody; Long, Kimberly et al. (2011) Amelogenesis imperfecta: genotype-phenotype studies in 71 families. Cells Tissues Organs 194:279-83
Wright, J Timothy; Hong, Sung P; Simmons, Darrin et al. (2008) DLX3 c.561_562delCT mutation causes attenuated phenotype of tricho-dento-osseous syndrome. Am J Med Genet A 146:343-9
Haldeman, Ryan J; Cooper, Lyndon F; Hart, Thomas C et al. (2004) Increased bone density associated with DLX3 mutation in the tricho-dento-osseous syndrome. Bone 35:988-97
Hart, P Suzanne; Wright, J Timothy; Savage, Mathew et al. (2003) Exclusion of candidate genes in two families with autosomal dominant hypocalcified amelogenesis imperfecta. Eur J Oral Sci 111:326-31
Pallos, D; Hart, P S; Cortelli, J R et al. (2001) Novel COL1A1 mutation (G559C) [correction of G599C] associated with mild osteogenesis imperfecta and dentinogenesis imperfecta. Arch Oral Biol 46:459-70
Von Kap-Herr, C; Kandala, G; Mann, S S et al. (2000) Assignment of PDZ domain-containing protein GIPC gene (C19orf3) to human chromosome band 19p13.1 by in situ hybridization and radiation hybrid mapping. Cytogenet Cell Genet 89:234-5
Ravassipour, D B; Hart, P S; Hart, T C et al. (2000) Unique enamel phenotype associated with amelogenin gene (AMELX) codon 41 point mutation. J Dent Res 79:1476-81
Mann, S S; Hart, T C; Pettenati, M J et al. (1999) Assignment of the sodium-dependent dicarboxylate transporter gene (SLC13A2 alias NaDC-1) to human chromosome region 17p11.1-->q11.1 by radiation hybrid mapping and fluorescence in situ hybridization. Cytogenet Cell Genet 84:89-90
Price, J A; Wright, J T; Walker, S J et al. (1999) Tricho-dento-osseous syndrome and amelogenesis imperfecta with taurodontism are genetically distinct conditions. Clin Genet 56:35-40