The Genetics of Polymicrogyria and Epilepsy

描述（由申请人提供）：儿科人群中多达一半的难治性癫痫发作与大脑皮层畸形有关。最近的研究表明，许多这些畸形是由缺陷基因的作用造成的。本项目的长期目标是确定一种特定的神经发育障碍，双侧额顶多小脑回症（BFPP）的遗传缺陷。这种最近发现的临床和神经放射学综合征是由于双侧额叶和顶叶皮质畸形，而其余皮质相对完好。该提案的目标是确定BFPP基因，并研究该基因在皮质发育中的作用。我们的初步工作将BFPP位点定位于染色体（ch）16q12.2-21。进一步的研究表明G蛋白偶联受体56（GPR 56）是ch 16 - 1连接的BFPP的潜在基因。拟议的实验将需要进一步表征BFPP综合征和描绘GPR 56在皮质发育中的作用。具体目标包括：1）分析BFPP和BFPP样综合征的遗传和临床方面，2）BFPP家族中GPR 56的突变分析和3）GPR 56表达的时间和空间模式的表征和小鼠遗传模型的产生以检查GPR 56在体内皮质发育中的作用。 申请人是一名MD/PhD，已完成儿科住院医师和儿科学奖学金。她获得了分子和细胞生物学博士学位，研究野生型和突变Kit受体的致癌特性。她的导师是克里斯托弗·A。沃尔什说，他是霍华德休斯的一名调查员，负责监督一个资金充足、设备齐全的人类和小鼠大脑皮层发育和遗传学实验室。该研究计划的重点是扩大候选人的知识1）遗传图谱和特定的人类大脑畸形的连锁分析和2）皮质发育的神经遗传学和分子观点。

DESCRIPTION (provided by applicant): As many as half of intractable seizures in the pediatric population are associated with malformations of the cerebral cortex. Recent studies have shown that many of these malformations result from the action of defective genes. The long-term objective of this project is to identify genetic defect of a specific neurological developmental disorder, bilateral frontoparietal polymicrogyria (BFPP). This recently identified clinical and neuroradiographic syndrome is due to bilateral malformation of the frontal and parietal cortex, while the remaining cortex is relatively spared. The goal of this proposal is to identify the gene for BFPP and study the role of this gene in cortical development. Our preliminary work mapped the BFPP locus to chromosome (ch) 16q12.2-21. Further studies suggested G protein-coupled receptor 56 (GPR56) is the potential gene for ch16-1inked BFPP. The proposed experiments will entail further characterization of BFPP syndrome and delineation of the role of GPR56 in cortical development. The Specific Aims include: 1) analyze genetic and clinical aspects of BFPP and BFPP-like syndromes, 2) mutational analysis of GPR56 in BFPP families and 3) characterization of the temporal and spatial pattern of GPR56 expression and generation of a mouse genetic model to examine the role of GPR56 in cortical development in vivo. The applicant is an MD/PhD who has completed her pediatric residency and neonatology fellowship. She earned her doctoral degree in molecular and cell biology studying the oncogenic properties of the wild type and mutated Kit receptors. Her mentor is Christopher A. Walsh, a Howard Hughes investigator who oversees a well-funded, well-equipped human and mouse cortical development and genetics laboratory. The research plan focuses on expanding candidate's knowledge of 1) genetic mapping and linkage analysis of a specific human brain malformation and 2) neurogenetics and molecular perspectives of cortical development.