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

高通量基因分型和 DNA 测序研究人类疾病的遗传贡献：牙釉质形成的遗传学 (Hu)

• 批准号: 10023801
• 负责人: KIM DOHENY
• 金额: $ 8.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-30 至 2021-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023801
• 关键词: Address; Affect; Ameloblasts; Amelogenesis Imperfecta; Appearance; Bioinformatics; Biological; Blindness; Body part; Bulla; Candidate Disease Gene; Cells; Chemicals; Clinical; Complex; Computer Simulation; Conscious; Consumption; Contracts; Cystic Fibrosis; DNA Sequence Alteration; DNA sequencing; Defect; Dental; Dental Enamel; Dentition; Development; Diagnosis; Disease; Duchenne muscular dystrophy; Enamel Formation; Environment; Etiology; Family; Family Sizes; Family member; Financial Hardship; Food; Frequencies; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic screening method; Genetic study; Genomic DNA; Genotype; Gingival Fibromatosis; Goals; Health; Hereditary Disease; Heritability; Human; Human Cell Line; Immunologic Deficiency Syndromes; Individual; Inferior; Inheritance Patterns; Inherited; Insurance; Kidney; Knockout Mice; Manuals; Medical; Membrane Proteins; Molecular; Molecular Chaperones; Muscular Dystrophies; Mutation; Nephrocalcinosis; Oral; Oral cavity; Organ; Pain; Pathologic; Pathology; Patients; Pharmacogenomics; Phenotype; Physical Examination; Play; Population Study; Prevention; Procedures; Proteins; Quality of life; Recording of previous events; Rehabilitation therapy; Reporting; Research; Research Personnel; Research Proposals; Sequence Alignment; Shapes; Skin; Syndrome; Testing; Time; TimeLine; Tissues; Tooth structure; Translations; Validation; Variant; base; calcification; causal variant; cost; dental genetics; disease-causing mutation; endoplasmic reticulum stress; exome; exome sequencing; gene interaction; genetic element; high throughput technology; human disease; impression; improved; insight; kindred; loss of function; malformation; mutant; novel; outcome forecast; permanent tooth; premature; prevent; prospective; protein misfolding; psychologic; reconstruction; recruit; screening; secondary analysis; self esteem; small molecule; tool; vector

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.

遗传的搪瓷畸形是由牙齿形成必不可少的基因缺陷引起的，并将其分组在一起，以ameleogenesis of Amelogenesosis implfecta或AI的集体指定为组合。 AI是严重的状况，可能与身体其他部位的健康问题有关。由于牙齿的毁容外观，AI患者通常是自觉的。他们的自尊心较低，并认为自己的生活质量较低。他们避免冷食和饮料。有些人接受了广泛的牙科康复程序，但大多数人只是遭受了疾病的影响。 AI的形式多种，每种形式是由不同基因中的缺陷引起的。在AI的综合征形式中，搪瓷畸形伴随着严重的，有时是隐藏的全身问题，例如失明，肾脏钙化，免疫缺陷或皮肤泡得很泡。 AI的分离和综合症形式通常无法在临床上区分，因此鉴定出病因缺陷的基因测试将确定诊断并辨别除了牙釉质外是否受到其他组织或器官的影响。更好地了解AI的原因为改善AI疾病的诊断，预后，治疗和治愈的诊断，评估和治疗提供了希望。某些突变导致蛋白质的合成过早停止，可能会通过“读取”分子来治疗。其他基因缺陷会导致与蛋白质错误折叠有关的细胞病理，而不是与蛋白质的功能丧失有关。化学伴侣可以防止导致分泌或膜蛋白不正确折叠的突变引起的细胞病理。在这项研究中，我们检验以下三个假设：1）全异位分析可以鉴定出牙釉质缺陷在已久经考验的AI候选基因中的牙釉质缺陷中的因果突变，并鉴定出新型的AI引起的基因和突变。 2）在相应的敲除（KO）小鼠中的牙釉质畸形（KO）小鼠中的证明可以支持在AI亲属中鉴定出的新基因缺陷的因果关系。 3）某些AI是由潜在可逆的病理机制引起的。为了检验这些假设，我们提出了以下两个特定目的：SA 1：确定新的基因和突变，这些基因和突变，这些基因和突变会导致AI属性中遗传的搪瓷缺陷。 SA 2：确定引起AI的过早翻译终止或ER应力是否可逆。意义：确定引起遗传搪瓷缺陷的基因将允许基因检测诊断AI，改善对患者预后的评估，并识别可以用化学伴侣或读取分子进行治疗的突变，以促进患有遗传有缺陷的患者的正常牙齿发育。背景。