CLEIDOCRANIAL DYSPLASIA DENTAL PHENOTYPE AND GENOTYPE CORRELATIONS

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DESCRIPTION (provided by applicant): RUNX2 is a critical master transcription factor for bone formation. RUNX2 mutations are associated with the human autosomal dominant (AD) disease cleidocranial dysplasia (CCD, OMIM #119600). CCD patients presents with skeletal defects such as clavicle agenesis and short stature as well as dental defects including supernumerary teeth. Mice with targeted Runx2 gene deletion (Runx2 ) mimics the skeletal defects of CCD showing complete lack of bone formation, but not the major CCD dental phenotype of supernumerary teeth as seen in humans. In fact, Runx2 mice show early arrested tooth formation (bud/cap stage). Therefore, since mice have only a single dentition, the mouse Runx2 phenotype varies significantly from that seen in human CCD patients. Thus, it is critical to study the function of RUNX2 in human dental tissues related to CCD. The long-range goal of this application is to understand the role of RUNX2 during human tooth formation and how specific RUNX2 mutations cause formation of a third dentition for application in tooth regeneration. The short-term aim of this application is to study the genotype-phenotype correlation of genetic variation in CCD patients related to their dental findings through utilization of unique human CCD dental cell lines. The hypothesis of this application is that specific RUNX2 mutations occurring within the functional domain of this protein lead to characteristic alterations in human dentition associated with unique patterns in tooth number and tooth morphology/structure. Specific Aim1 is to correlate the dental phenotype of identified CCD families with their genotype and Specific Aim 2 is to establish stable dental pulp cell lines from developing tooth organs of CCD patients with or without defined RUNX2 mutations. This study could correlate precise RUNX2 mutations with dental phenotypes and establish the unique resource of human CCD dental cell lines with characterized RUNX2 mutations. These studies could ultimately foster new strategies for tooth replacement therapies in addition to increasing our understanding of tooth formation and genetic diseases altering tooth patterning. PUBLIC HEALTH RELEVANCE: The project is to study the role of RUNX2 in tooth formation by survey the relationship between dental phenotype and genotype of genetic defects in cleidocranial dysplasia (CCD) and to establish stable pulp cells from CCD patients with characterized RUNX2 or other genetic defects.