The Genetics of Polymicrogyria and Epilepsy

描述(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，这些畸形中的许多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--双侧额顶顶小脑回(BFPP)--的遗传缺陷。这一新近确诊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所致，而其余皮质相对幸免。这项建议的目的是确定BFPP的基因，并研究该基因在皮质发育中的作用。我们的初步工作将BFPP基因座定位于染色体(Ch)16q12.2-21。进一步研究表明，G蛋白偶联受体56(GPR56)是CH16-1连锁BFPP的潜在基因。拟议的实验将需要对BFPP综合征进行进一步的表征，并描述GPR56在皮质发育中的作用。具体目标包括：1)分析BFPP和BFPP样综合征的遗传学和临床方面；2)BFPP家族中GPR56的突变分析；3)GPR56表达的时空模式的表征和小鼠遗传模型的建立，以检测GPR56在活体皮质发育中的作用。 申请者为医学博士，已完成儿科住院医师和新生儿科研究员学位。她获得了分子和细胞生物学的博士学位，研究野生型和突变的Kit受体的致癌特性。她的导师是霍华德·休斯的研究员克里斯托弗·A·沃尔什，他负责管理一个资金充足、设备齐全的人类和小鼠皮质发育和遗传学实验室。研究计划的重点是扩大候选人的知识，1)特定人类大脑畸形的基因图谱和连锁分析，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.