Genetic Mechanisms of Amelogenesis Imperfecta

釉质生成不完善的遗传机制

• 批准号: 10453477
• 负责人: JAN Ching Chun HU
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453477
• 关键词: Acid Phosphatase; Address; Affinity Chromatography; Ameloblasts; Amelogenesis; Amelogenesis Imperfecta; Biological; Blindness; Candidate Disease Gene; Cell Communication; Clinical; Collection; Consultations; DNA; Defect; Dental; Dental Enamel; Dental Records; Deterioration; Diagnosis; Disease; Early Diagnosis; Early Intervention; Enamel Formation; Epilepsy; Exhibits; Failure; Family; Feedback; GPR68 gene; Gene Expression; Gene Mutation; Gene Proteins; Gene Targeting; Gene-Modified; Generations; Genes; Genetic; Genetic Counseling; Genetic Diseases; Genetic Predisposition to Disease; Genetic study; Health; Hereditary Disease; Human; Immunologic Deficiency Syndromes; In Situ Hybridization; Inherited; Integrin beta Chains; Intervention; Kidney; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; LAMC2 gene; Ligand Binding; Ligands; Manuscripts; Mass Spectrum Analysis; Maturation-Stage Ameloblast; Medical; Medical Genetics; Molecular; Mus; Mutation; National Institute of Dental and Craniofacial Research; Odontogenesis; Oral; Orphan; Paper; Participant; Pathogenicity; Pathologic; Patients; Phenotype; Phosphoproteins; Physicians; Play; Prognosis; Proteins; Publishing; Recording of previous events; Regulation; Research; Role; STIM1 gene; Sequence Analysis; Skin; Statistical Data Interpretation; Syndrome; System; Testing; Therapeutic Intervention; Time; Tumor Necrosis Factor Receptor; Variant; Writing; accurate diagnosis; ameloblastin; amelogenin; base; calcification; causal variant; craniofacial; deciduous tooth; disease-causing mutation; exome; experience; genetic disorder diagnosis; genetic pedigree; genetic testing; genetic variant; improved; insight; interest; loss of function; malformation; mouse model; novel; proband; receptor; recruit; transcriptome; transcriptome sequencing

Amelogenesis imperfecta (AI) is a diverse collection of about 90 inherited conditions all manifesting enamel malformations, and each caused by defects in a different gene. Many AI cases are isolated (only exhibit enamel defects). Others are syndromic. The syndromes can involve very serious health problems, including blindness, kidney calcifications, immunodeficiency, skin fragility, epilepsy, etc. Primary teeth start to erupt at 6 months so enamel defects are often an early sign of a larger disease, and the only apparent phenotype at the time of diagnosis. As some systemic conditions can be mitigated by early medical intervention, an early and accurate diagnosis can minimize the effects of the condition on the patient's health. Without an accurate genetic diagnosis, early intervention to mitigate pending systemic deterioration cannot be employed. A barrier to making a genetic diagnosis of AI conditions is incomplete knowledge of the genes and mutations that can cause isolated and syndromic forms of AI. This barrier is addressed in SA1: to recruit and characterize AI families to determine their genetic etiology, identify new causative genes and mutations, and facilitate genetic testing. Once an AI proband is identified, a pedigree is constructed, and mode of inheritance assessed. Medical and dental histories are reviewed and dental records obtained. If a non-dental phenotype is ascertained, a medical consultation is coordinated with the physician. Subject DNA is characterized by whole-exome sequence (WES) analyses. WES analyses cover about 85% of all disease-causing mutations. Advances made in SA1 will increase knowledge of the genes and mutations that cause AI, enhance clinical genetic counseling, and result in practical advancements in gene-based testing, diagnosis, and intervention to improve patient prognoses. Until recently the greatest barrier to understanding the molecular mechanisms of dental enamel formation was a lack of knowledge of the critical molecular participants. Genetics has identified many new critical genes/proteins, so now the greatest barrier is understanding their functions. This barrier is addressed in SA2: to generate and characterize mouse models with defects homologous to human mutations to validate genetic discoveries, and define normal and disease mechanisms. Specific hypotheses are tested in wild-type and genetically modified mice concerning the normal function and pathological consequences of a loss of function of four genes critical for dental enamel formation: odontogenesis associated phosphoprotein (Odaph), acid phosphatase 4 (Acp4), RELT tumor necrosis factor receptor (Relt), and integrin beta 6 (Itgb6). OdaphC41*/C41* mice show a specific failure of post-secretory transition (PST) of ameloblasts into maturation, offering unique opportunities to understand the molecular mechanisms of PST. ACP4 is distinguished as either a lysosomal or secreted protein. The ligand that binds the RELT receptor is identified. The role of ITGß6 in matrix-cell interactions governing regulation of amelogenin expression is determined. The long term objective is to improve the diagnosis and management of AI conditions and to eventually to cure them.

牙釉质发育异常（AI）是一个多样化的集合，约90遗传条件都表现出牙釉质 畸形，每一种都是由不同基因的缺陷引起的。许多AI病例是孤立的（仅显示釉质 缺陷）。其他人是综合征。这些综合征可能会导致非常严重的健康问题，包括失明， 肾脏钙化、免疫缺陷、皮肤脆弱、癫痫等。乳牙在6个月大时开始萌出， 牙釉质缺损通常是较大疾病的早期迹象，并且是牙釉质缺损时唯一明显的表型。 诊断.由于一些全身性疾病可以通过早期医疗干预来缓解， 诊断可以最大限度地减少病情对患者健康的影响。如果没有准确的基因诊断， 不能采用早期干预来缓解即将出现的系统性恶化。一个基因制造的障碍 AI条件的诊断是基因和突变的不完全知识，可以导致孤立和 AI的综合征形式SA 1中解决了这一障碍：招募和表征AI家族，以确定其 遗传病因学，确定新的致病基因和突变，并促进基因检测。 一旦确定了AI先证者，就构建了一个谱系，并评估了遗传模式。医疗和 审查牙科历史并获得牙科记录。如果确定了非牙齿表型， 咨询与医生协调。受试者DNA的特征在于全外显子组序列（WES） 分析。WES分析涵盖了约85%的致病突变。在SA 1中取得的进展将增加 了解导致AI的基因和突变，加强临床遗传咨询，并导致实际的 在基因检测、诊断和干预方面取得进展，以改善患者的健康状况。 直到最近，理解牙釉质形成的分子机制的最大障碍 是缺乏对关键分子参与者的了解。遗传学已经发现了许多新的关键 基因/蛋白质，所以现在最大的障碍是了解它们的功能。这一障碍在SA 2中得到解决： 生成和表征具有与人类突变同源的缺陷的小鼠模型，以验证遗传学 发现，并定义正常和疾病的机制。在野生型和非野生型中测试特定假设。 基因修饰小鼠的正常功能和功能丧失的病理后果， 牙釉质形成的四个关键基因：牙形成相关磷蛋白（Odaph），酸性磷酸酶， 磷酸酶4（Acp 4）、RELT肿瘤坏死因子受体（Relt）和整联蛋白β 6（Itgb 6）。OdaphC41*/C41* 小鼠表现出成釉细胞分泌后转变（PST）成熟的特定失败，提供了独特的 有机会了解PST的分子机制。ACP 4被区分为溶酶体或 分泌蛋白鉴定结合RELT受体的配体。ITG β 6在基质细胞中的作用 确定了支配釉原蛋白表达调节的相互作用。长期目标是改善 AI病症的诊断和管理，并最终治愈它们。

项目成果

Phenotypic variability in LAMA3-associated amelogenesis imperfecta.

LAMA3 相关的釉质形成不全的表型变异。

• DOI: 10.1111/odi.14425
• 发表时间: 2023
• 期刊: Oral diseases
• 影响因子: 3.8
• 作者: Wang,Shih-Kai;Zhang,Hong;Wang,Yin-Lin;Seymen,Figen;Koruyucu,Mine;Simmer,JamesP;Hu,JanC-C
• 通讯作者: Hu,JanC-C