Genetics of Dental Enamel Formation

牙釉质形成的遗传学

• 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
• 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

 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（由申请人提供）：遗传性牙釉质畸形是由牙釉质形成所必需的基因缺陷引起的，并被归类为釉质发育不全或AI的统称。AI是一种严重的疾病，可能与身体其他部位的健康问题有关。人工智能患者往往是自我意识，因为他们的牙齿毁容外观。他们的自尊心较低，认为自己的生活质量较差。他们避免冷的食物和饮料。有些人接受了广泛的牙科康复程序，但大多数人只是遭受疾病的影响。AI有多种形式，每种形式都是由不同基因的缺陷引起的。在AI的综合征形式中，釉质畸形伴随着严重的，有时是隐藏的系统性问题，如失明，肾钙化，免疫缺陷或皮肤起泡。AI的孤立和综合征形式通常无法在临床上区分，因此识别致病遗传缺陷的基因检测将建立诊断并辨别除釉质外的其他组织或器官是否受到影响。更好地了解AI的原因为改善AI疾病的诊断、预后评估、治疗和治愈提供了希望。一些突变导致蛋白质合成过早停止，这可能会被“通读”分子治疗。其他基因缺陷导致与蛋白质错误折叠相关的细胞病理学，而不是蛋白质功能丧失。化学分子伴侣可以防止由导致分泌蛋白或膜蛋白不正确折叠的突变引起的细胞病理学。在本研究中，我们验证了以下三个假设：1）全外显子组分析可以识别已证实的AI候选基因中的釉质缺损相关基因突变，也可以识别新的AI致病基因和突变。2)在AI激酶中鉴定的新基因缺陷的因果关系可以通过相应敲除（KO）小鼠中的釉质畸形的证明来支持。3)一些AI是由潜在可逆的病理机制引起的。为了验证这些假设，我们提出了以下两个具体目标：SA 1：确定新的基因和突变，导致遗传性牙釉质缺陷的AI激酶。SA 2：确定AI引起的过早翻译终止或ER应激是否可逆。重要性：识别导致遗传性牙釉质缺陷的基因将允许基因测试来诊断人工智能，改善对患者预后的评估，并识别可以用化学伴侣或通读分子治疗的突变，以促进遗传背景缺陷患者的正常牙齿发育。