The Genetics of Polymicrogyria and Epilepsy

描述（由申请人提供）：在儿童人群中，多达一半的顽固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。该项目的长期目标是确定一种特殊的神经发育障碍，双侧额顶叶多小回症（BFPP）的遗传缺陷。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层的畸形，而其余的皮层相对完好。本研究的目的是鉴定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位点定位在染色体（ch） 16q12.2-21上。进一步的研究表明G蛋白偶联受体56 （GPR56）是ch16-1连接的BFPP的潜在基因。拟议的实验将需要进一步表征BFPP综合征和描述GPR56在皮质发育中的作用。具体目的包括：1)分析BFPP和BFPP样综合征的遗传和临床方面；2)分析BFPP家族中GPR56的突变；3)表征GPR56表达的时空格局并建立小鼠遗传模型，以研究GPR56在体内皮质发育中的作用。

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.