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

描述（由申请人提供）：几条证据暗示自闭症、癫痫和精神分裂症可能共享一些潜在的大脑异常。最近的遗传学研究表明，CNTNAP 2的基因产物Caspr2的突变增加了这些常见表现的疾病风险。在蛋白质水平上，Caspr2在啮齿动物外周神经系统中的作用得以确立。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定位的信息。最近的研究表明，Caspr2是细胞间相互作用的关键分子，对正常神经元功能和皮质发育很重要。为了了解该蛋白的结构及其在人脑中的功能，我们提出以下几点：1）研究Caspr2胞外区的三维结构。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，从而为未来癫痫和自闭症的药物靶标鉴定奠定基础。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引起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提供基础。

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.