Genetics of Dental Enamel Formation

牙釉质形成的遗传学

基本信息

批准号：
8886196
负责人：
JAN Ching Chun HU
金额：
$ 46.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886196
关键词：
Accounting Address Affect Ameloblasts Amelogenesis Imperfecta Appearance Biological Blindness Body part Bulla Candidate Disease Gene Cells Chemicals Child Clinical Collection Conscious County DNA Sequence Alteration Defect Dental Dental Enamel Dentists Development Diagnosis Disease Enamel Formation Etiology Exhibits Family Food Future Gene Mutation General Population Genes Genetic Genetic Predisposition to Disease Genetic screening method Genomic DNA Grant Health Human Cell Line Ice Cream Immunologic Deficiency Syndromes Individual Inferior Inheritance Patterns Inherited Kidney Knockout Mice Life Medical Medical Genetics Membrane Proteins Michigan Mission Molecular Chaperones Mutation Oral Oral cavity Organ Pain Pathology Patients Persons Phenotype Physical Examination Pigments Prevention Procedures Proteins Quality of life Recording of previous events Recruitment Activity Rehabilitation therapy Reporting Research Research Proposals Research Support Running STIM1 gene Skin Stress Surveys Syndrome Testing Tissues Tooth structure Translations United States National Institutes of Health Validation Variant calcification clinical phenotype drinking exome genetic disorder diagnosis genetic linkage analysis genetic pedigree human disease improved kindred loss of function malformation mutant novel outcome forecast premature prevent proband prospective protein misfolding public health relevance reconstruction segregation self esteem vector

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（通过应用程序证明）：继承的搪瓷畸形是由牙科形成必不可少的基因缺陷引起的，并且是ped ped the the nimperfecta的集体设计，而它们的自尊心较低。生活质量。他们避免了一些饮料。像失明，肾脏钙化，免疫缺陷或皮肤泡得很厉害。 AI的原因为蛋白质的诊断合成提供了希望，可以通过“读取”分子来停止蛋白质，这可能会导致与蛋白质丧失有关的细胞病理。在本研究中，蛋白质折叠不当。在AI中，可以通过相关敲除（KO）小鼠中的搪瓷畸形来支持。由AI引起的交易终止是可逆的。背景。