A MULTICENTER STUDY OF IDIOPATHIC GENERALIZED EPILEPSY

我们在寻找青少年首发的特发性全面性癫痫的遗传病因方面取得了显著进展。 (IGE)。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)标识了 Cr.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)已确定的病例- ME2基因内含子1的控制序列差异。4)表明抑制大脑中的ME2增加了 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)发现母体 链接数据和种群数据中的EJM1继承。7)显示BRD2含有不寻常的内含子 在其他印迹基因中看到的富含GC区域的序列。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)找到了 关于儿童缺勤的具体联系。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 鉴定易感基因；2)分析ME2中的mRNA加工，以检测内含子1的发现。3)学习 检测免疫球蛋白E患者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的表达变异。4)利用SNP和SNP检测已鉴定基因之间的相互作用 单倍型数据。5)确定5号和8号染色体上的基因。6)测试已确定的基因是否为Ige易感基因 通过寻找非洲裔美国人和中南部地区的关联，发现非欧洲族群中的基因座 美国血统的IGE患者。7)确定ME2是否会增加其他形式的特发性疾病的易感性 癫痫(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，我们可以， 在下一个授权期，比以往任何时候都更接近了解IGE的一些原因。ME2基因座 这一发现尤其可能为癫痫药物的开发提供新的方向。

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 susceptbility genotypes; 2) Analyze mRNA processing in ME2 to test the intron 1finding. 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.