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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：
8148639
负责人：
THOMAS C HART
金额：
$ 82.97万
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/8148639
关键词：
Cystinosis Cytology Deglutition Dental Enamel Dental Pulp Dental caries Dentin Diagnosis Disease Genetic Human craniofacial

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 study 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 vitro cell models to study disease pathogeneses. Progress during the last year is reported below. Mutant DLX 3 disrupts odontoblast polarization and dentin formation Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker, caspase-3, were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of Runx2, Wnt 10A, and TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism. In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology. Craniofacial and dental findings in cystinosis Cystinosis is a rare autosomal recessive lysosomal storage disorder with developmental and mineralization anomalies as part of its clinical presentation. The objective of this study was to provide the first systematic assessment of the craniofacial and dental characteristics associated with cystinosis. Oral and radiographic evaluations were performed on 73 patients with cystinosis. Analyses of cephalometry (n = 20), taurodontism (n = 47), caries (n = 47), enamel defects (n = 48), soft tissue anomalies (n = 48), and dental age (n = 41) were performed on the cystinosis group, and compared with age- and sex-comparable controls or standards. Cystinosis patients manifested relative mandibular deficiency, an increased facial height, and a reduced airway space. Taurodontism and enamel defects were significantly more prevalent in cystinosis patients compared with controls (P < 0.0001 and P = 0.027, respectively). Children (aged <15 years) with cystinosis also demonstrated a significant delay, of almost 9 months, of their dental development (P < 0.001). Novel craniofacial and dental features are associated with cystinosis. Craniofacial deficiencies may influence the swallowing and respiratory complications seen in cystinosis. Renal pathology and associated mineral imbalance may explain the dental root and enamel anomalies found in cystinosis patients; the developmental delays in cystinosis include delayed dental formation. Novel cathepsin C mutation in a Brazilian family with Papillon-Lefvre syndrome: case report and mutation update Papilion-Lefevre syndrome (PLS) is a rare autosomal recessive disorder that involves palmoplantar keratosis (PK) and severe aggressive periodontitis. Cathepsin C (CTSC) gene mutations are etiologic for PLS, with more than 60 different mutations reported in different ethnic groups worldwide. The purpose of this study was to report a novel cathepsin C mutation in a Brazilian patient. A 4-year-old boy presented with aggressive periodontitis, recession, missing teeth, and hyperkeratosis of the palms of hands and soles. Peripheral blood samples were obtained from family members for genomic DNA isolation. The coding region and exon/intron boundaries of the CTSC gene were amplified and sequenced. The patient had a PLS phenotype, which included PK and early-onset severe periodontitis. Sequence analysis showed a novel CTSC mutation (c.267-268del) present in the homozygous state. This report described a novel mutation in a family with Brazilian Papillon-Lefvre syndrome and presented a review of all cathepsin C (65) mutations reported to date. Oral rehabilitation of a patient with amelogenesis imperfecta. Amelogenesis imperfecta is a hereditary disorder that causes defective enamel development in the primary and permanent teeth. Clinical treatment is important to address the esthetic appearance of affected teeth, reduce dentinal sensitivity, preserve tooth structure, and optimize masticatory function. The purpose of this case report was to describe the diagnosis, treatment planning, and dental rehabilitation of a patient with autosomal recessive amelogenesis imperfecta. The patient was followed for 5 years, and evaluation 3 years after restorations revealed no pathology associated with the rehabilitation. The patient's esthetic and functional expectations were satisfied.

我们的工作范式是，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。我们研究孟德尔疾病是为了识别潜在的基因缺陷，并了解该/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）和体外细胞模型来研究疾病发病机制。去年的进展报告如下。突变体 DLX 3 破坏成牙本质细胞极化和牙本质形成毛齿骨（TDO）综合征是一种常染色体显性遗传疾病，其特征是骨骼和牙齿的厚度和密度异常。大多数 TDO 病例的病因是 Distal-Less 3 (DLX3) 基因中的 4 bp 缺失突变。为了研究突变体 DLX3 (MT-DLX3) 对牙本质发育的体内作用，我们生成了由小鼠 2.3 Col1A1 启动子驱动的表达 MT-DLX3 的转基因 (TG) 小鼠。所有牙齿的牙本质缺陷在放射学上都很明显，TG 小鼠的非矿化牙髓尺寸增大，这与 TDO 患者的临床特征一致。高分辨率射线照相、微型计算机断层扫描和扫描电镜显示，MT-DLX3 TG 小鼠的矿化牙本质区域减少，牙本质小管的数量和组织异常。组织学和免疫组织化学研究表明，牙本质减少伴随着成牙本质细胞细胞学的改变，包括成牙本质细胞极化的破坏和成牙本质细胞数量的减少。 TUNEL 分析表明成牙本质细胞凋亡增强。 TG 小鼠的成牙本质细胞以及转染 MT-DLX3 cDNA 的成牙本质细胞样 MDPC-23 细胞中凋亡标记物 caspase-3 的表达水平增加。 Runx2、Wnt 10A 和 TBC1D19 的表达与成牙本质细胞中的 DLX3 表达共定位，并且 MT-DLX3 显着降低了所有三个基因的表达。 TBC1D19 在细胞极性中发挥作用，TBC1D19 表达减少可能导致观察到的成牙本质细胞极性破坏和细胞凋亡。这些数据表明，MT-DLX3 会破坏成牙本质细胞的细胞分化，导致成牙本质细胞凋亡，以及牙本质小管形成和牙本质基质产生的畸变，从而导致牙本质减少和牛牙病。总之，该TG模型表明MT-DLX3对牙本质和骨中的基质产生和矿化具有不同的影响，并为成牙本质细胞生物学的研究提供了一种新工具。胱氨酸病的颅面和牙齿表现胱氨酸沉积症是一种罕见的常染色体隐性遗传溶酶体贮积症，其临床表现包括发育和矿化异常。本研究的目的是首次系统评估与胱氨酸病相关的颅面和牙齿特征。对 73 名胱氨酸病患者进行了口腔和放射学评估。对胱氨酸病组进行头影测量（n = 20）、牛牙症（n = 47）、龋齿（n = 47）、牙釉质缺陷（n = 48）、软组织异常（n = 48）和牙齿年龄（n = 41）分析，并与年龄和性别可比较的对照或标准进行比较。胱氨酸中毒患者表现出相对的下颌缺损、面部高度增加和气道空间缩小。与对照组相比，胱氨酸病患者的牛牙症和牙釉质缺陷更为普遍（分别为 P < 0.0001 和 P = 0.027）。患有胱氨酸中毒的儿童（年龄 <15 岁）的牙齿发育也表现出显着延迟，近 9 个月（P < 0.001）。新的颅面和牙齿特征与胱氨酸病有关。颅面缺陷可能会影响胱氨酸病中出现的吞咽和呼吸系统并发症。肾脏病理学和相关的矿物质失衡可以解释胱氨酸病患者的牙根和牙釉质异常；胱氨酸病的发育迟缓包括牙齿形成迟缓。巴西 Papillon-Lefvre 综合征家族中的新型组织蛋白酶 C 突变：病例报告和突变更新 Papilion-Lefevre 综合征 (PLS) 是一种罕见的常染色体隐性遗传疾病，涉及掌跖角化症 (PK) 和严重的侵袭性牙周炎。组织蛋白酶 C (CTSC) 基因突变是 PLS 的病因，全球不同种族中报告了 60 多种不同的突变。本研究的目的是报告一名巴西患者的新型组织蛋白酶 C 突变。一名 4 岁男孩因侵袭性牙周炎、退缩、牙齿缺失、手掌和脚底角化过度就诊。从家庭成员处获取外周血样本，用于分离基因组 DNA。 CTSC 基因的编码区和外显子/内含子边界被扩增并测序。该患者具有 PLS 表型，其中包括 PK 和早发性严重牙周炎。序列分析显示新的 CTSC 突变 (c.267-268del) 以纯合状态存在。该报告描述了巴西 Papillon-Lefvre 综合征家族中的一种新突变，并对迄今为止报告的所有组织蛋白酶 C (65) 突变进行了回顾。牙釉质生成不全患者的口腔康复。釉质生成不全是一种遗传性疾病，会导致乳牙和恒牙牙釉质发育缺陷。临床治疗对于改善受影响牙齿的美观、降低牙本质敏感性、保留牙齿结构和优化咀嚼功能非常重要。本病例报告的目的是描述常染色体隐性遗传性釉质生成不全症患者的诊断、治疗计划和牙科康复。对患者进行了 5 年的随访，修复后 3 年的评估显示没有与康复相关的病理。患者的审美和功能期望得到满足。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development.

DOI：
10.1016/j.ydbio.2008.10.014
发表时间：
2009-01-01
期刊：
Developmental biology
影响因子：
2.7
作者：
Choi SJ;Roodman GD;Feng JQ;Song IS;Amin K;Hart PS;Wright JT;Haruyama N;Hart TC
通讯作者：
Hart TC

Enamel defects and salivary methylmalonate in methylmalonic acidemia.

DOI：
10.1111/j.1601-0825.2008.01509.x
发表时间：
2009-04
期刊：
Oral diseases
影响因子：
3.8
作者：
Bassim CW;Wright JT;Guadagnini JP;Muralidharan R;Sloan J;Domingo DL;Venditti CP;Hart TC
通讯作者：
Hart TC

Oral rehabilitation of a patient with amelogenesis imperfecta.

牙釉质生成不全患者的口腔康复。