Caspr2 as an autism candidate gene: a proteomic approach to function & structure.

Caspr2 作为自闭症候选基因：功能的蛋白质组学方法

基本信息

批准号：
8041617
负责人：
Davide Comoletti
金额：
$ 31.2万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8041617
关键词：
Adhesives Affect Amino Acid Substitution Attention deficit hyperactivity disorder Autistic Disorder Biochemical Biological Process Biology Brain Candidate Disease Gene Cell Adhesion Molecules Cell Communication Cells Coculture Techniques Code Collaborations Complex Copy Number Polymorphism Crystallography Data Databases Deuterium Development Dimensions Disease Drug Delivery Systems Electron Microscopy Epilepsy Excitatory Synapse Extracellular Domain France Functional disorder Future Genes Genetic Genetic Polymorphism Gilles de la Tourette syndrome Hippocampus (Brain)Human Hydrogen Language Delays Link Location Molecular Mutation Mutation Analysis NRCAM gene Negative Staining Neuraxis Neurodevelopmental Disorder Neurons Pathogenesis Patients Peripheral Nervous System Population Process Property Protein Biosynthesis Proteins Proteomics Ranvier&apos s Nodes Research Personnel Resolution Rodent Roentgen Rays Role Schizophrenia Severities Site Staging Structure Synapses Synaptic Potentials System TAG-1 axonal glycoprotein Technology Therapeutic Therapeutic Intervention Work autism spectrum disorder base contactin design disorder risk genetic linkage improved insight instrumentation mutant neuroligin 1 neuroligin 3 neuronal cell body particle protein function protein structure protein transport research study three dimensional structure trafficking

项目摘要

DESCRIPTION (provided by applicant): Several lines of evidence imply that autism, epilepsy, and schizophrenia may share some underlying brain abnormalities. Recent genetic studies suggest that mutations of Caspr2, gene product of CNTNAP2, increase the disease risk of these common manifestations. At the protein level, the role of Caspr2 in the rodent peripheral nervous system is established. In the human CNS, however, no information on the role of this protein and its neuronal location is thus far available. Recent studies suggest that Caspr2 is a key molecule in cell-cell interactions important for normal neuronal function and cortical development. To understand the structure of this protein and its functions in the human brain, we propose the following: 1) Study the three-dimensional structure of the extracellular domain of Caspr2. As the atomic structure of a protein drives its function, Caspr2 structure will enable us to improve our understanding of the biology of this neuronal protein and to predict how mutations linked to a disease state affect Caspr2 structure and function, thus setting the basis for future drug targets identification for epilepsy and autism. 2) Investigate the role of Caspr2 in hippocampal neurons and the biochemical and cellular consequences of mutations of human Caspr2 linked to ASD. Because mutations found in the human population affect the biological function of Caspr2, analysis of these mutations promises to yield critical insights into the neuronal anomalies that give rise to aberrations in neuronal connectivity, and may provide a basis for designing specific therapeutic interventions. PUBLIC HEALTH RELEVANCE: Several lines of evidence indicate that autism, epilepsy, ADHD, Tourette syndrome, and schizophrenia share some common underlying brain abnormalities. Recent genetic studies suggest that mutations or copy number variation in the CNTNAP2 gene may cause some of these manifestations. The studies of the structure and the deleterious effects of the known mutations of Caspr2 (gene product of CNTNAP2) will help understanding the biology of this neuronal protein and predict how mutations linked to a disease state affect Caspr2 structure and function. Ultimately, these data will help researchers to develop therapeutic strategies to modify protein biosynthesis, processing, or adhesive properties of the partnering proteins to ameliorate these disorders.

描述（由申请人提供）：多项证据表明自闭症、癫痫症和精神分裂症可能存在一些潜在的大脑异常。最近的遗传学研究表明，Caspr2（CNTNAP2 的基因产物）的突变会增加这些常见表现的疾病风险。在蛋白质水平上，Caspr2 在啮齿动物周围神经系统中的作用已被确立。然而，在人类中枢神经系统中，迄今为止还没有关于这种蛋白质的作用及其神经元位置的信息。最近的研究表明 Caspr2 是细胞间相互作用的关键分子，对于正常神经元功能和皮质发育非常重要。为了了解该蛋白的结构及其在人脑中的功能，我们提出以下建议：1）研究Caspr2胞外域的三维结构。由于蛋白质的原子结构驱动其功能，Caspr2 结构将使我们能够提高对这种神经元蛋白质生物学的理解，并预测与疾病状态相关的突变如何影响 Caspr2 结构和功能，从而为未来的药物奠定基础癫痫和自闭症的目标识别。 2) 研究 Caspr2 在海马神经元中的作用以及与 ASD 相关的人类 Caspr2 突变的生化和细胞后果。由于在人群中发现的突变会影响 Caspr2 的生物学功能，因此对这些突变的分析有望对导致神经元连接异常的神经元异常产生重要的见解，并可能为设计特定的治疗干预措施提供基础。公共健康相关性：多项证据表明，自闭症、癫痫症、注意力缺陷多动症、抽动秽语综合症和精神分裂症具有一些共同的潜在大脑异常。最近的遗传学研究表明，CNTNAP2 基因的突变或拷贝数变异可能导致其中一些表现。对 Caspr2（CNTNAP2 的基因产物）已知突变的结构和有害影响的研究将有助于了解这种神经元蛋白的生物学，并预测与疾病状态相关的突变如何影响 Caspr2 的结构和功能。最终，这些数据将帮助研究人员制定治疗策略，以改变蛋白质生物合成、加工或配对蛋白质的粘附特性，从而改善这些疾病。