Inherited enamel malformations are caused by defects in genes essential for dental enamel formation and are grouped together under the collective designation of Amelogenesis Imperfecta, or AI. AI is a serious condition and may be associated with health problems in other parts of the body. AI patients are often self- conscious because of the disfiguring appearance of their teeth. They have lower self-esteem and perceive themselves as having an inferior quality of life. They avoid cold food and drinks. Some undergo extensive dental rehabilitation procedures, but the majorities simply suffer the effects of the disease. There are numerous forms of AI, each caused by defects in a different gene. In syndromic forms of AI, enamel malformations are accompanied by serious, sometimes hidden systemic problems, like blindness, kidney calcifications, immunodeficiency, or skin blistering. Isolated and syndromic forms of AI often cannot be distinguished clinically, so genetic testing that identifies the causative genetic defect would establish the diagnosis and discern whether or not other tissues or organs besides enamel are affected. Better understanding of the causes of AI provides hope for improvements in the diagnosis, assessment of prognosis, treatment, and cure of AI diseases. Some mutations cause synthesis of a protein to stop prematurely, which can potentially be treated with readthrough molecules. Other gene defects cause cell pathology related to protein misfolding rather than to a protein's loss of function. Chemical chaperones can prevent cell pathology resulting from mutations that cause secreted or membrane proteins to fold improperly. In this study we test the following three Hypotheses: 1) Whole-exome analyses can identify causal mutation(s) in kindreds with enamel defects in proven AI candidate genes, and also identify novel AI-causing genes and mutations. 2) Causality of novel gene defects identified in AI kindreds can be supported by the demonstration of enamel malformations in the corresponding knockout (KO) mice. 3) Some AI is caused by potentially reversible pathological mechanisms. To test these hypotheses we propose the following two Specific Aims: SA 1: Identify novel genes and mutations that cause inherited enamel defects in AI kindreds. SA 2: Determine if AI-causing premature translation termination or ER stress is reversible. Significance: Identifying the genes that cause inherited enamel defects will permit genetic testing to diagnose AI, improve assessment of the patients' prognoses, and recognize mutations that can be treated with chemical chaperones or readthrough molecules to promote normal tooth development in patients with a defective genetic background.

Public Health Relevance

The objective of this research is to improve the diagnosis, prognosis assessment, and treatment of patients with Amelogenesis Imperfecta, or AI. We enlist the help of AI families to pinpoint the genetic mutations that cause their diseases. Understanding the genetic causes of AI helps clinicians diagnose AI in their patients. With hopes of developing new treatments for AI, we investigate the abilities of chemical chaperones and readthrough molecules to alleviate the pathology that causes enamel malformations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015846-15
Application #
9626894
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Stein, Kathryn K
Project Start
2004-04-01
Project End
2020-02-28
Budget Start
2019-03-01
Budget End
2020-02-28
Support Year
15
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
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

Showing the most recent 10 out of 73 publications