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Genetic Studies of Human Craniofacial Diseases

人类颅面疾病的遗传学研究

基本信息

批准号：
7733926
负责人：
THOMAS C HART
金额：
$ 196.92万
依托单位：
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7733926
关键词：
Affect Age-Years Aging Alkaline Phosphatase Amelogenesis Imperfecta Amino Acids Animal Model Area Bicuspid Biochemical Biology Bone Density Cell Differentiation process Cell model Cells Cessation of life Characteristics Child Cleaved cell Clinical Clinical Protocols Code Collagen Collagen Gene Collagen Type I Complex Condition Craniosynostosis Cultured Cells Defect Deletion Mutation Dental Dental Enamel Dental Enamel Hypoplasia Dental Papilla Dental Pulp Dentin Dentin Dysplasia Dentinogenesis Imperfecta Deposition Desmin Development Diagnosis Diagnostic Disease Disruption Dorsal Eczema Enamel Formation Endopeptidases Event Exhibits Exons Face Family Family Study Forehead Fostering Frameshift Mutation Gene Expression Gene Mutation Gene Proteins Genes Genetic Genetic screening method Gingiva Goals Hair Hard Palate Hereditary Disease Human Hypodontia IgE Image Immunohistochemistry Immunologic Deficiency Syndromes Immunologics In Vitro Individual Infection Institutes Job&apos s Syndrome Keratosis Knockout Mice Laboratories Lesion Leukoplakia Lip structure Mesenchymal Minerals Modeling Molecular Biology Molecular Profiling Mus Mutation Myocardial Infarction Natural History Nonsense Mutation Nose Numbers Odontoblasts Oral Oral mucous membrane structure Osteocalcin Palate Pathogenesis Pathologic Pathological fracture Patients Peptide Hydrolases Peptide Signal Sequences Phenotype Population Process Progeria Proteins RNA Splicing Range Recruitment Activity Recurrence Reporting Research Personnel Serum Site Skeletal system Splice-Site Mutation Stroke Structure Surface Syndrome TDO2 gene Testing Thick Tissues Tongue Tooth eruption Tooth structure Transfection Transgenic Mice Transgenic Model United States National Institutes of Health Work base bone clinical Diagnosis craniofacial deciduous tooth design gene environment interaction human disease in vivo insight interest kindred mineralization mouse model mutant novel promoter protein expression scoliosis soft tissue tool trait tricho-dento-osseous syndrome

项目摘要

Our working paradigm is that there is a genetic basis to human disease and that understanding the genetic basis of disease will foster development of better diagnostic and treatment strategies. We Mendelian diseases to identify the underlying gene defect and to understand how the product(s) of this/these gene mutation(s) result in abnormal development or disease. In some cases we have developed animal models (transgenic mice) and in virto cell models to study disease pathogeneses. Dentinogenesis imperfecta (DI) (15% effort): Genetic mutations of the dentin sialophosphosphoprotein (DSSP) gene are responsible for DI and dentin dysplasia (DD). Dentin, the most abundant tissue in teeth, is produced by odontoblasts, which differentiate from mesenchymal cells of the dental papilla. Dentin defects are broadly classified into two major types: DIs, types I-III and dentin dysplasias (DDs, types I and II). To date, mutations in DSPP have been found to underlie DI types II and III and DD type II. With the elucidation of the underlying genetic mechanisms has come the realization that the clinical characteristics associated with DSPP mutations appear to represent a continuum of phenotypes. (Hart & Hart 2007). Recent work (McKnight et al 2008) describing studies of 9 families segregating DI or DD has substantiated that the clinical characteristics associated with DSPP mutations appear to represent a continuum of phenotypes. Within nine DDtype II and DI type II and III patients, seven have 1 of 4 net -1 deletions within the approximately 2-kb coding repeat domain of the DSPP gene while the remaining two patients have splice-site mutations. All frameshift mutations are predicted to change the highly soluble DSPP protein into proteins with long hydrophobic amino acid repeats that could interfere with processing of normal DSPP and/or other secreted matrix proteins. We propose that all previously reported missense, nonsense, and splice-site DSPP mutations (all associated with exons 2 and 3) result in dominant phenotypes due to disruption of signal peptide-processing and/or related biochemical events that also result in interference with protein processing. Amelogenesis Imperfecta (AI) (30%effort): We continue to study families segregating the AI phenotype. AI is caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These models provide tools for understanding enamel formation and AI pathogenesis. We determined human AI phenotypes in a clinical population of 463 AI affected individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes identified. The majority of human mutations for genes coding enamel nonproteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and defective mineral crystal structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are similar to those in humans. Mmp20 null mice have a greater degree of hypoplasia than humans with MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions.(Wright et al 2008). Not all AI causing mutations have been identified. We studied 8 Turkish kindreds with autosomal dominant hypoplastic AI and identified FAM83H mutations in all 8 families. A total of 3 different FAM83H nonsense mutations; a p.Q398X mutation and 2 novel nonsense mutations, p.Q444X and p.Q456X, were detected. These findings indicate that FAM83H mutations may be responsible for the majority of autosomal dominant hypocalcified amelogenesis imperfecta in the Turkish population. As the most predominant form of autosomal dominant AI, these findings have important implications for the implementation of genetic testing to confirm this clinical diagnosis. (Hart et al 2008 In Press). TDO studies-45%effort:Tricho-dento-osseous syndrome (TDO) due to DLX3 mutations is characterized by anomalies of tooth, hair and bone. A cardinal feature of TDO is an increased thickness and density of bone. We tested the effects of the DLX3 gene mutation responsible for TDO on the osteoblastic differentiation of preosteoblastic MC3T3E1 cells and multipontent mesenchymal C2C12 cells. Transfection of wild type DLX3 into MC3T3E1 and C2C12 cells increased alkaline phosphatase-2 activity, mineral deposition, and promoter activities of the osteocalcin and type 1 collagen genes. Transfection of mutant DLX3 into these cells further enhanced alkaline phosphatase activity, mineral deposition, and osteocalcin promoter activities, but did not further enhance type 1 collagen promoter activity. Transfection of mutant DLX3 into C2C12 cells markedly down regulated desmin gene expression, and protein expression of desmin and MyoD, while increasing protein expression of osterix and Runx2. These results demonstrate that the DLX3 deletion mutation associated with TDO enhances mesenchymal cell differentiation to an osteoblastic lineage. (Choi et al 2008). As in vitro findings do not always recapitulate the true in vivo biology, we generated a transgenic model with mice carrying the 4bp DLX3 mutation driven by a collagen 1A1 promoter. Studies are ongoing to characterize the biologic mechanism by which this DLX3 mutation results in beneficial bone changes and pathologic changes in the enamel, dentin and pulp. We have characterized dental/oral and craniofacial findings in a number of rare genetic syndromes (10% effort) Hyperimmunoglobulin-E syndrome (HIES) is a primary immunodeficiency characterized by eczema, recurrent infections, and extremely elevated serum immunoglobulin-E. Non-immunologic findings include characteristic facial features (prominent forehead, fleshy nasal tip, and increased interalar distance); skeletal involvement (pathological fractures, scoliosis, and craniosynostosis); and retention of primary teeth. We characterized intraoral soft tissue findings in 60 HIES patients. Our study revealed the presence of lesions of the hard palate and dorsal tongue in 55% and 60% of patients, respectively. Palatal lesions ranged from a generalized surface keratosis to a midline sagittal fibrotic bridge. Tongue lesions consisted of multiple fissures and a midline cleft. On the lip and buccal mucosa, keratotic plaques and/or surface fissures were found in 8% and 23% of patients, respectively. Manifested in 76.7% of patients, the intraoral lesions were significantly more prevalent than the characteristic facial traits (P=0.0013). These findings indicate that alterations in oral mucosa and gingiva were present in the majority of HIES patients. These novel intraoral findings may facilitate the diagnosis of HIES. (Domingo et al 2008). Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome withpremature aging, generally leading to death at 13 years of age due to myocardial infarction or stroke. We participated in a multi institute NIH study to characterize the natural history of progeria patients. 15 children representing nearly half of the world's known patients with Hutchinson-Gilford progeria syndrome were evaluated as part of a comprehensive clinical protocol at NIH. Oral abnormalities characterized included hypodontia (most often, missing second premolars), tongue-tie, high arch palate, double rows of teeth, and delayed tooth eruption. (Merideth et al 2

我们的工作模式是，人类疾病有遗传基础，了解疾病的遗传基础将促进更好的诊断和治疗策略的发展。我们通过孟德尔疾病来确定潜在的基因缺陷，并了解这个/这些基因突变的产物如何导致异常发育或疾病。在某些情况下，我们开发了动物模型（转基因小鼠）和虚拟细胞模型来研究疾病的发病机制。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta.

DOI：
10.1186/1746-160x-3-8
发表时间：
2007-01-31
期刊：
Head & face medicine
影响因子：
3
作者：
Santos, Maria C L G;Hart, P Suzanne;Line, Sergio R P
通讯作者：
Line, Sergio R P

Characterization of fibroblasts with Son of Sevenless-1 mutation.

具有 Sevenless-1 突变之子的成纤维细胞的表征。

DOI：
10.1177/154405910608501115
发表时间：
2006
期刊：
Journal of dental research
影响因子：
7.6
作者：
Lee,EJ;Jang,SI;Pallos,D;Kather,J;Hart,TC
通讯作者：
Hart,TC

Effect of the interleukin-1 genotype on outcomes of regenerative periodontal therapy with bone replacement grafts.

IL-1 基因型对骨替代移植再生牙周治疗结果的影响。

DOI：
10.1902/jop.2004.75.10.1335
发表时间：
2004
期刊：
Journal of periodontology.
影响因子：
0
作者：
Weiss,OrenI;Caton,Jack;Blieden,Timothy;Fisher,SusanG;Trafton,Sarah;Hart,ThomasC
通讯作者：
Hart,ThomasC

Craniofacial and dental phenotype of Smith-Magenis syndrome.

史密斯-马吉尼斯综合征的颅面和牙齿表型。