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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015846-07
Application #
7938856
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (09))
Program Officer
Scholnick, Steven
Project Start
2004-04-13
Project End
2014-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$370,949
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Smith, Charles E; Hu, Yuanyuan; Hu, Jan C-C et al. (2018) Quantitative analysis of the core 2D arrangement and distribution of enamel rods in cross-sections of mandibular mouse incisors. J Anat :
Kim, Youn Jung; Seymen, Figen; Kang, Jenny et al. (2018) Candidate gene sequencing reveals mutations causing hypoplastic amelogenesis imperfecta. Clin Oral Investig :
Koruyucu, M; Kang, J; Kim, Y J et al. (2018) Hypoplastic AI with Highly Variable Expressivity Caused by ENAM Mutations. J Dent Res 97:1064-1069
Kim, Youn Jung; Kang, Jenny; Seymen, Figen et al. (2017) Analyses of MMP20 Missense Mutations in Two Families with Hypomaturation Amelogenesis Imperfecta. Front Physiol 8:229
Pham, Cong-Dat; Smith, Charles E; Hu, Yuanyuan et al. (2017) Endocytosis and Enamel Formation. Front Physiol 8:529
Klein, Ophir D; Duverger, Olivier; Shaw, Wendy et al. (2017) Meeting report: a hard look at the state of enamel research. Int J Oral Sci 9:e3
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
Núñez, Stephanie M; Chun, Yong-Hee P; Ganss, Bernhard et al. (2016) Maturation stage enamel malformations in Amtn and Klk4 null mice. Matrix Biol 52-54:219-233
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
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

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