Clinical and Molecular Studies of Malformations

畸形的临床和分子研究

基本信息

批准号：
7968913
负责人：
Leslie Biesecker
金额：
$ 161.22万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
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/7968913
关键词：
Amish Animal Model Biochemical Breeding Candidate Disease Gene Case Study Cells Clinical Clinical Research Protocols Clove Congenital Abnormality Defect Development Diagnostic Diagnostic radiologic examination Disease Disease model Drosophila genus Electroencephalography Etiology Functional disorder GLI3 gene Genes Genetic Heart Diseases Hereditary Disease Homologous Gene Human Human Genetics Image Knockout Mice Laboratories Lenz syndrome 2 Link Lipomatosis Literature Maps Microcephaly Microphthalmos Molecular Molecular Biology Molecular Genetics Mus Mutation Natural History Operative Surgical Procedures Other Genetics Pallister-Hall syndrome Pathogenesis Patients Phenocopy Phenotype Physical Examination Polydactyly Predisposition Proteins Proteus Proteus Syndrome Pulmonary function tests Recording of previous events Series Severities Surveys Syndrome Techniques Technology Transgenic Organisms Translational Research Ultrasonography Walker-Warburg syndrome Zebrafish disease-causing mutation malformation mutant novel positional cloning research clinical testing tissue/cell culture tomography tool tumor

Amish Animal Model Biochemical Breeding Candidate Disease Gene Case Study Cells Clinical Clinical Research Protocols Clove Congenital Abnormality Defect Development Diagnostic Diagnostic radiologic examination Disease Disease model Drosophila genus Electroencephalography Etiology Functional disorder GLI3 gene Genes Genetic Heart Diseases Hereditary Disease Homologous Gene Human Human Genetics Image Knockout Mice Laboratories Lenz syndrome 2 Link Lipomatosis Literature Maps Microcephaly Microphthalmos Molecular Molecular Biology Molecular Genetics Mus Mutation Natural History Operative Surgical Procedures Other Genetics Pallister-Hall syndrome Pathogenesis Patients Phenocopy Phenotype Physical Examination Polydactyly Predisposition Proteins Proteus Proteus Syndrome Pulmonary function tests Recording of previous events Series Severities Surveys Syndrome Techniques Technology Transgenic Organisms Translational Research Ultrasonography Walker-Warburg syndrome Zebrafish disease-causing mutation malformation mutant novel positional cloning research clinical testing tissue/cell culture tomography tool tumor

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项目摘要

The laboratory uses a translational research approach to study human malformations. In the clinical arena, we operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that we are currently studying include Pallister-Hall, Greig cephalopolysyndactyly, McKusick Kaufman, non-syndromic polydactyly, Proteus, Bardet-Biedl, Lenz microphthalmia, and Oculofaciocardiodental syndromes. We use the tools of modern molecular biology to determine the molecular pathogenesis of these disorders. These include positional cloning, microarray expression and microarray CGH analysis, cell and tissue culture studies to assess cell biologic functions and abnormalities of gene products, and the creation and analysis of animal models of human genetic disease (mouse and zebrafish). Using these techniques we have elucidated the etiology of Pallister-Hall, McKusick-Kaufman, Lenz microphthalmia and Oculofaciocardiodental syndromes. In addition, we have demonstrated the functional defect of Pallister-Hall syndrome by comparing the function of the causative gene in that disorder (GLI3) to its Drosophila homologue (cubitus interruptus) and correlating those functions with mutations in over 150 patients. In so doing, we have determined that the mechanism of Pallister Hall syndrome is distinct from that of Greig cephalopolysyndactyly syndrome. We have also clinically redefined the Proteus syndrome, a disorder of mosaic overgrowth with tumor susceptibility. We did this through evaluating a series of 35 patients and an exhaustive survey of all cases reported in the literature. This allowed us to establish new clinical diagnostic criteria for this disorder and delineate two novel disease entities, the hemihyperplasia-multiple lipomatosis syndrome and CLOVE syndrome. In our studies of Lenz microphthalmia syndrome we determined that this disorder is actually an amalgamation of two distinct X-linked diseases and that one form of Lenz is allelic to Oculofaciocardiodental syndrome and that both of these diseases are caused by mutations in the BCOR gene. Finally, we are using animal models to study two disorders, Amish microcephaly syndrome, which we determined to be caused by mutations in the DNC gene, and a phenocopy of Greig cephalopolysyndactyly syndrome. For Amish microcephaly, we have created a mouse knockout model of that disease using transgenic technology and are studying the pathophysiology of that disorder using genetic and biochemical analysis. We are also performing a positional cloning analysis of the Greig cephalopolysyndactyly phenotype in the mouse using a sporadic mutant identified at a large breeding facility. This disorder has now been mapped to a 500 KB interval and candidate genes are being sequenced.

实验室使用转化研究方法来研究人类畸形。在临床领域，我们运行了几种临床研究方案，以评估多效性发育异常的严重程度，畸形谱和自然历史的范围。我们使用包括病史和体格检查的临床评估，包括射线照相，超声和断层扫描以及脑电图，肺功能测试等的成像研究，以表征功能和结构异常。在选定的情况下，如果它们提供临床益处，并可以提高我们对正在研究的疾病的理解，我们还可以进行手术治疗。我们目前正在研究的某些疾病包括Pallister-Hall，Greig Cephalophyndactyly，McKusick Kaufman，非综合性多态度，Proteus，Bardet-Biedl，Lenz Microphtllmia和Oculofaciofaciarofaciarofaciarofaciocararmia和oculofaciocarardiodental consyndromes。我们使用现代分子生物学的工具来确定这些疾病的分子发病机理。其中包括位置克隆，微阵列表达和微阵列CGH分析，细胞和组织培养研究，以评估基因产物的细胞生物学功能和异常，以及人类遗传疾病（小鼠和斑马鱼）动物模型的创建和分析。使用这些技术，我们阐明了Pallister-Hall，McKusick-Kaufman，Lenz Microphthalmia和Oculofaciocardiodental综合征的病因。此外，我们通过比较该疾病（GLI3）与其果蝇同源物（Cubitus Intruptus）的功能，证明了Pallister-Hall综合征的功能缺陷，并将这些功能与150多名患者的突变相关联。这样一来，我们确定了Pallister Hall综合征的机理与Greig Cephalopolysyndactyly综合征的机制不同。我们还在临床上重新定义了Proteus综合征，Proteus综合征是一种具有肿瘤敏感性的镶嵌过度生长的疾病。我们通过评估了一系列35名患者和对文献报道的所有病例进行详尽的调查来做到这一点。这使我们能够为这种疾病建立新的临床诊断标准，并描绘了两个新型疾病实体，即半血肿 - 多脂瘤病综合征和丁香综合征。在我们对LENZ微心理综合征的研究中，我们确定这种疾病实际上是两种不同的X连锁疾病的融合性，而Lenz的一种形式是Oculofaciocardiodental综合征的等位基因，并且这两种疾病都是由Bcor Gene中的突变引起的。最后，我们正在使用动物模型研究两种疾病，即阿米什小头畸形综合征，我们确定是由DNC基因突变引起的，以及Greig Cephalopyndactyly综合征的表观。对于阿米什小头畸形，我们使用转基因技术创建了该疾病的小鼠敲除模型，并正在使用遗传和生化分析研究该疾病的病理生理学。我们还使用在大型育种设施上鉴定出的零星突变体进行了小鼠中Greig头孢菌的表型的位置克隆分析。现在，该疾病已被映射到500 kb的间隔，并且正在测序候选基因。