Patients with inherited enamel or dentin defects, because of the disfiguring appearance of their teeth, have low self-esteem and perceive themselves as having an inferior quality of life. Their teeth are painful: they avoid hot foods, cold drinks and ice cream. One 9-year-old girl with defective enamel told us that ice cream hurts like """"""""when you bump your elbow wrong"""""""". Advancing our understanding of normal and pathological tooth formation provides the best long-term hope for improvements in the diagnosis, treatment, and cure of inherited dental diseases. In this study we test the following three Hypotheses: 1) Defects in the genes encoding specialized enamel and dentin proteins cause amelogenesis imperfecta and dentinogenesis imperfecta or dentin dysplasia, respectively. 2) Genome-wide searches and candidate gene approaches can efficiently identify genes involved in the etiology of inherited dental disorders. 3) Characterizing the ameloblast transcriptome and the enamel and dentin proteomes will identify proteins critical for enamel and dentin formation and improve our understanding of the molecular mechanisms of normal and pathologic tooth formation. To test these hypotheses we propose the following two Specific Aims: SA 1: Identify genes and mutations that cause inherited defects of enamel and dentin. SA 2: Isolate and characterize molecules in the extracellular matrices of developing enamel and dentin. Approach: We recruit families with non-syndromic inherited defects of enamel and dentin, characterize their phenotypes, and perform mutation analyses on candidate genes to identify their causes. When possible we will perform genome-wide searches or joined analyses to link a small part of the genome to the dental disease. New candidate genes are identified by characterizing the ameloblast transcriptome and by performing proteomic analyses of the enamel and dentin extracellular matrices, which also characterize the proteins'structures. Significance: Identifying the full set of genes that cause non-syndromic inherited defects of enamel and dentin will change the ways we classify, diagnose, and perceive these disorders. The list of candidate genes that might cause the disease in a presenting family will be prioritized using established genoptype- phenotype correlations. As treatment outcomes are evaluated in persons with defined mutations, the success or failure of procedures such as enamel or dentin bonding may correlate with which gene is mutated, leading to improvements in treatment planning. Future genetic analyses may link genetic changes in these genes to susceptibility for dental caries and provide insights into mechanisms of tooth formation.
There is a group of specialized genes that are required to make the dentin and enamel layers of our teeth. Mutations that interfere with the normal expression of these genes cause disfiguring, painful, malformations of the teeth. The objective of our research is to identify these genes and to determine their function. Accomplishing the proposed study will improve the understanding and management of inherited dental defects.
|Hu, Yuanyuan; Smith, Charles E; Richardson, Amelia S et al. (2016) MMP20, KLK4, and MMP20/KLK4 double null mice define roles for matrix proteases during dental enamel formation. Mol Genet Genomic Med 4:178-96|
|NÃºÃ±ez, Stephanie M; Chun, Yong-Hee P; Ganss, Bernhard et al. (2016) Maturation stage enamel malformations in Amtn and Klk4 null mice. Matrix Biol 52-54:219-33|
|Parry, David A; Smith, Claire E L; El-Sayed, Walid et al. (2016) Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta. Am J Hum Genet 99:984-990|
|Smith, Charles E; Hu, Yuanyuan; Hu, Jan C-C et al. (2016) Ultrastructure of early amelogenesis in wild-type, Amelx(-/-), and Enam(-/-) mice: enamel ribbon initiation on dentin mineral and ribbon orientation by ameloblasts. Mol Genet Genomic Med 4:662-683|
|Hu, Yuanyuan; Smith, Charles E; Cai, Zhonghou et al. (2016) Enamel ribbons, surface nodules, and octacalcium phosphate in C57BL/6 Amelx(-/-) mice and Amelx(+/-) lyonization. Mol Genet Genomic Med 4:641-661|
|Wang, Shih-Kai; Hu, Yuanyuan; Yang, Jie et al. (2016) Fam83h null mice support a neomorphic mechanism for human ADHCAI. Mol Genet Genomic Med 4:46-67|
|Yang, Jie; Kawasaki, Kazuhiko; Lee, Moses et al. (2016) The dentin phosphoprotein repeat region and inherited defects of dentin. Mol Genet Genomic Med 4:28-38|
|Seymen, Figen; Kim, Youn Jung; Lee, Ye Ji et al. (2016) Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta. Am J Hum Genet 99:1199-1205|
|Wang, Shih-Kai; Hu, Yuanyuan; Yang, Jie et al. (2015) Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation. Mol Genet Genomic Med 3:302-19|
|Herzog, Curtis R; Reid, Bryan M; Seymen, Figen et al. (2015) Hypomaturation amelogenesis imperfecta caused by a novel SLC24A4 mutation. Oral Surg Oral Med Oral Pathol Oral Radiol 119:e77-81|
Showing the most recent 10 out of 67 publications