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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Small, Rochelle K
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University of North Carolina Chapel Hill
Schools of Dentistry
Chapel Hill
United States
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Wright, J Timothy (2010) Oral manifestations in the epidermolysis bullosa spectrum. Dermatol Clin 28:159-64
Wright, J T; Frazier-Bowers, S; Simmons, D et al. (2009) Phenotypic variation in FAM83H-associated amelogenesis imperfecta. J Dent Res 88:356-60
Wright, J Timothy; Hart, Thomas C; Hart, P Suzanne et al. (2009) Human and mouse enamel phenotypes resulting from mutation or altered expression of AMEL, ENAM, MMP20 and KLK4. Cells Tissues Organs 189:224-9
Moffatt, Pierre; Smith, Charles E; St-Arnaud, Rene et al. (2006) Cloning of rat amelotin and localization of the protein to the basal lamina of maturation stage ameloblasts and junctional epithelium. Biochem J 399:37-46
Wright, J Timothy (2006) The molecular etiologies and associated phenotypes of amelogenesis imperfecta. Am J Med Genet A 140:2547-55
Wright, J Tim; Daly, Bill; Simmons, Darrin et al. (2006) Human enamel phenotype associated with amelogenesis imperfecta and a kallikrein-4 (g.2142G>A) proteinase mutation. Eur J Oral Sci 114 Suppl 1:13-7; discussion 39-41, 379
Coffield, Kristina D; Phillips, Ceib; Brady, Melissa et al. (2005) The psychosocial impact of developmental dental defects in people with hereditary amelogenesis imperfecta. J Am Dent Assoc 136:620-30
Ozdemir, D; Hart, P S; Firatli, E et al. (2005) Phenotype of ENAM mutations is dosage-dependent. J Dent Res 84:1036-41
Ravassipour, Darren B; Powell, Cynthia M; Phillips, Ceib L et al. (2005) Variation in dental and skeletal open bite malocclusion in humans with amelogenesis imperfecta. Arch Oral Biol 50:611-23
Nusier, Mohamad; Yassin, Othman; Hart, Thomas C et al. (2004) Phenotypic diversity and revision of the nomenclature for autosomal recessive amelogenesis imperfecta. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:220-30

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