A MULTICENTER STUDY OF IDIOPATHIC GENERALIZED EPILEPSY

描述(申请人提供)：我们在寻找青少年首发的特发性全面性癫痫(IGE)的遗传病因方面取得了显著进展。在上一次资助期间，我们：1)在CHRS上发现了5个Ige连锁的基因座。5p、5q、6、8和18.2)鉴定出CHR。18基因作为苹果酸酶2(ME2)，使其对多种形式的免疫球蛋白E易感。3)确定了ME2基因内含子1的病例对照序列差异。4)显示抑制脑内ME2可增加神经兴奋性。5)鉴定出与人类白细胞抗原连锁的JME CHR。6位点(EJM1)为BRD2基因。6)在连锁数据和群体数据中发现了EJM1的母系遗传。7)发现BRD2含有不同寻常的内含子序列，在其他印记基因中发现了富含GC的区域。8)BRD2基因敲除小鼠的研制。9)原位杂交结果表明，在发育过程中BRD2在脑内高度表达。10)在CHR上发现了童年缺勤的特定关联。病例对照和基于家庭的数据均为5P。我们将利用这些发现来实现以下新目标：1)对ME2内含子1中的SNPs进行分类，以确定易感基因类型；2)分析ME2中的mRNA处理，以检验内含子1的发现。3)研究IgE患者来源的ME2的酶活性，并与对照组的活性进行比较。3)检测脑组织中ME2表达变异体。4)利用SNP和单倍型数据检验已识别的基因之间的相互作用。5)确定5号染色体和8号染色体上的基因。6)通过寻找非洲裔美国人和中南美洲人起源的IGE患者的关联，检验所确定的基因是否为非欧洲种族的IGE易感基因。7)确定ME2是否增加了对其他形式的特发性癫痫的易感性(例如，罗兰迪克病、童年缺勤等)。对两个，很快还有第三个(5p基因)免疫球蛋白E易感基因的识别表明，在下一个资助期，我们可以比以往任何时候都更接近了解一些免疫球蛋白E的病因。ME2位点的发现尤其可能为癫痫药物的开发提供新的方向。

DESCRIPTION (provided by applicant): We made notable progress in finding the genetic causes of adolescent-onset idiopathic generalized epilepsy (IGE). During the last grant period, we: 1) Found 5 IGE-linked loci on chrs. 5p, 5q, 6, 8, & 18. 2) Identified the chr. 18 gene as malic enzyme 2 (ME2), conferring susceptibility to several forms of IGE. 3) Identified case-control sequence differences in intron 1 of ME2. 4) Showed that inhibiting ME2 in brain increases neuroexcitability. 5) Identified the HLA-linked JME chr. 6 locus (EJM1) as the BRD2 gene. 6) Found maternal inheritance of EJM1 in linkage data and population data. 7) Showed BRD2 contains unusual intronic sequences with GC-rich regions seen in other imprinted genes. 8) Development of a BRD2 knockout mouse. 9) Showed BRD2 is highly expressed in brain during development using in-situ hybridization. 10) Found a childhood absence-specific association on chr. 5p in both case-control and family based data. We will exploit these findings to accomplish the following new aims: 1) Categorize SNPs in intron 1 of ME2 to identify susceptibility genotypes; 2) Analyze mRNA processing in ME2 to test the intron 1 finding. 3) Study the enzymatic activity of ME2 derived from IGE patients and compare to activity from control subjects. 3) Test for ME2 expression variants in brain. 4) Test for interaction between the identified genes using SNP and haplotype data. 5) Identify genes on chromosomes 5 and 8. 6) Test if identified genes are IGE susceptibility loci in non-European ethnic groups by looking for association in African-American and Central/South American-origin IGE patients. 7) Determine whether ME2 increases susceptibility to other forms of idiopathic epilepsy (e.g. Rolandic, childhood absence, etc.). The identification of two, and soon a third (the 5p gene), IGE susceptibility genes suggests that we can, in the next grant period, come closer than ever before to understanding some causes of IGE. The ME2 locus findings especially may suggest new directions for epilepsy drug development.