Genetic Mechanisms of Amelogenesis Imperfecta

釉质生成不完善的遗传机制

基本信息

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
项目类别：
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

项目摘要

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.

Amelogenesis imperfecta（AI）是一所多元化的大学，大约有90个遗传条件畸形，每种畸形是由不同基因中的缺陷引起的。缺陷）。肾脏钙化，免疫缺陷，皮肤脆弱，癫痫等。搪瓷缺陷通常是较大疾病的早期迹象，也是唯一的明显表型诊断作为某些系统状况可以通过早期医疗干预来缓解诊断可以最大程度地减少病情对患者健康的影响。早期干预以减轻未决的全身恶化。 AI条件的诊断是对可以分离和分离的基因和突变的不完全了解。 AI的综合征形式。遗传病因，鉴定新的病因和突变，并促进基因检测。医学和医学审查牙科历史，并获得牙齿记录。咨询与医师协调。分析。了解引起AI的基因和突变，增强临床遗传咨询并导致实际基于基因的测试，诊断和干预的进步，以改善患者预后。直到最近，最大的障碍是理解牙齿搪瓷形成的分子机制缺乏批判参与者的遗传学。基因/蛋白质，现在最大的障碍是理解其功能。生成和表征具有缺陷的小鼠模型发现并定义正常和疾病机制。关于正常功能和病理奉献丧失功能丧失的基因修饰的小鼠牙齿牙釉质形成至关重要的四个基因：牙本质发生相关的磷蛋白（ODAPH）磷酸酶4（ACP4），Relt肿瘤坏死因子受体（Relt）和整联蛋白β6（ITGB6）。小鼠表现出特定的分泌后过渡（PST）成熟的成熟的失败，提供独立性了解PST的分子机制的机会。分泌的蛋白质。相互作用的调节amelogenin表达是确定的。对AI条件的诊断和管理和治疗事件。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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