High Throughput Genotyping and DNA Sequencing for Studying the Genetic Contributions to Human Disease: Genetics of Dental Enamel Formation (Hu)

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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 majority 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.