A MULTICENTER STUDY OF IDIOPATHIC GENERALIZED EPILEPSY

特发性全身性癫痫的多中心研究

• 批准号: 7680490
• 负责人: DAVID A. GREENBERG
• 金额: $ 3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680490
• 关键词: Absence Epilepsy; Adolescent; Affect; African American; BRD2 gene; Biological Assay; Brain; Bromodomain Containing Protein 2; Candidate Disease Gene; Childhood; Chromosome Mapping; Chromosomes, Human, Pair 5; Data; Data Linkages; Databases; Development; Diagnostic; Dominican; Ensure; Epilepsy; Ethnic Origin; Ethnic group; Etiology; European; Family; GC Rich Sequence; Generalized Epilepsy; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome Scan; Genotype; Grant; Haplotypes; Heterogeneity; Hispanics; Human; Immunoglobulin Variable Region; In Situ Hybridization; Inherited; Introns; Juvenile Myoclonic Epilepsy; Knockout Mice; Knowledge; Link; Lymphocyte; Maps; Medical center; Messenger RNA; Metabolism; Multicenter Studies; Mus; Myoclonic Absence Epilepsies; Myoclonic Epilepsies; Neurons; Neurotransmitters; Odds Ratio; Patients; Phenotype; Play; Population; Population Group; Predisposition; Process; Production; Puerto Rican; Range; Reporting; Research; Risk; Role; Sampling; Scanning; Seizures; Slice; South American; Specificity; Statistical Models; Succinate Dehydrogenase; Susceptibility Gene; Syndrome; Testing; Tonic - clonic seizures; Variant; Work; base; case control; chromosome 5q loss; drug development; enzyme activity; gene interaction; imprint; malic enzyme; segregation

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.

我们在寻找癫痫发作的遗传原因方面取得了显著进展 （IGE）。在上一个研究期间，我们：1）在chrs上发现了5个与IgE连锁的位点。5 p，5 q，6，8和18。2)确定了 Chr. 18基因作为苹果酸酶2（ME 2），赋予对几种形式的IGE的易感性。3)已查明的案件- ME 2内含子1的控制序列差异。4)显示抑制脑中的ME 2增加 神经兴奋性5)将HLA连锁的JME chr.6位点（EJM 1）鉴定为BRD 2基因。6)发现产妇 EJM 1在连锁数据和群体数据中遗传。7)显示BRD 2含有不寻常的内含子 在其他印记基因中发现的富含GC的序列。8)BRD 2敲除小鼠的开发。 9)原位杂交显示BRD 2在发育过程中在大脑中高度表达。10)发现了一 在病例对照和基于家庭的数据中，儿童期缺失与chr.5p的特异性关联。 我们将利用这些发现来实现以下新的目标：1）对ME 2基因内含子1的SNPs进行分类 2）分析ME 2的mRNA加工过程，验证内含子1的发现。3)研究 来自IGE患者的ME 2的酶活性，并与来自对照受试者的活性进行比较。第三章 测试脑中的ME 2表达变体。4)使用SNP和SNP检测鉴定的基因之间的相互作用， 单倍型数据。5)识别染色体5和8上的基因。6)检测已识别基因是否为IGE易感基因 通过寻找非裔美国人和中/南部地区的关联， 美国籍IGE患者。7)确定ME 2是否增加对其他形式的特发性 癫痫（例如，Rolandic，儿童缺失等）。 两个IGE易感基因的鉴定，很快第三个（5 p基因），IGE易感基因的鉴定表明，我们可以， 在下一个资助期，比以往任何时候都更接近了解IGE的一些原因。ME 2基因座 这些发现可能为癫痫药物的开发提供新的方向。