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(申请人提供)：遗传性釉质畸形是由牙釉质形成所必需的基因缺陷引起的，并被归类为釉质发生不全，或AI。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。AI患者通常会因为牙齿的毁容而感到不自在。他们自尊心较低，认为自己的生活质量较低。他们不吃冷食，不喝冷饮。一些人接受了广泛的牙科康复程序，但大多数人只是遭受了这种疾病的影响。人工智能有多种形式，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，釉质畸形伴有严重的、有时是隐藏的全身性问题，如失明、肾脏钙化、免疫缺陷或皮肤起泡。孤立的和综合征形式的AI在临床上往往无法区分，因此，识别致病基因缺陷的基因检测将建立诊断，并识别除了釉质之外的其他组织或器官是否受到影响。对AI病因的更好理解为改进AI疾病的诊断、预后评估、治疗和治愈带来了希望。一些突变会导致蛋白质的合成提前停止，这可能会被“通读”分子处理。其他基因缺陷会导致与蛋白质错误折叠有关的细胞病理，而不是蛋白质功能的丧失。化学伴侣可以防止因导致分泌或膜蛋白不正确折叠的突变而导致的细胞病理。在本研究中，我们检验了以下三个假设：1)全外显子组分析可以在已证实的AI候选基因中牙釉质缺陷的家系中识别因果突变(S)，也可以识别新的导致AI的基因和突变。2)在AI家系中发现的新基因缺陷的因果关系可以通过相应的基因敲除(KO)小鼠中的釉质畸形来支持。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：识别导致AI家族遗传性釉质缺陷的新基因和突变。答案2：确定人工智能导致的提前翻译终止或ER应激是否可逆。意义：识别导致遗传性釉质缺陷的基因将使基因测试能够诊断AI，改善对患者预后的评估，并识别可以用化学伴侣或直读分子治疗的突变，以促进遗传背景缺陷患者的正常牙齿发育。