RESOLVING HETEROGENEITY IN EPILEPSY WITH GENETIC MARKERS

用遗传标记解决癫痫的异质性

• 批准号: 2037368
• 负责人: DAVID A. GREENBERG
• 金额: $ 76.92万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2037368
• 关键词: adolescence (12-20); blood chemistry; case history; chromosome disorders; disease /disorder classification; electroencephalography; family genetics; gene expression; generalized seizures; genetic markers; genetic polymorphism; histocompatibility typing; human genetic material tag; human population genetics; human subject; linkage mapping; major histocompatibility complex; myoclonus epilepsy; nervous system disorder epidemiology; neurogenetics; polymerase chain reaction; restriction fragment length polymorphism

This study will use linkage analysis to investigate the genetics of idiopathic generalized epilepsy (IGE), which accounts for more than 40% of all epilepsy. We will investigate three specific forms of IGE: juvenile myoclonic epilepsy (JME), epilepsy with awakening grand mal (AGM), and epilepsy with random grand mal (RGM). JME has been shown to be genetically linked to the HLA region of chromosome 6. This JME locus has been designated EJM-1. Because of the family characteristics of JME, it was thought that several other forms of IGC would be also be linked to the HLA locus. We tested this hypothesis during the last grant period. We found that RGM is apparently not linked to the HLA locus. However, AGM, although different from JME clinically, may be genetically identical. We have the following four goals for our further work on the genetics of IGE: 1. To test the hypothesis, developed in the last grant period, that AGM is linked to the HLA locus on chromosome 6. 2. To search for a gene locus that causes epilepsy with random grand mal (RGM) which we have shown to be genetically different from the clinically similar AGM and JME. 3. Simultaneously, to look for a second locus involved in the expression of all three forms of IGC. 4. To find flanking markers for the EJM-1 locus. We will recruit families identified through JME, RGM and AGM patients; collect blood, EEGs, and family histories from all family members; and type the subjects for markers throughout the genome. We will test for linkage of AGM to the HLA locus and test all three forms, but especially RGM, for linkage to a genetic marker. We will test specific candidate loci for linkage to any or all three forms of IGE. Our findings during the last grant period--that AGM may be linked to EJM- 1 and RGM is not linked -- show that genetic linkage data can be used to unravel clinical heterogeneity. They demonstrate that differentiating the different forms of epilepsy--one of the most difficult problems in both research and clinical practice -- can be resolved by searching for the genetic cause of disease. They also show that definition of the proper phenotype is critical for genetic studies of common complex disease.

本研究将利用连锁分析的方法来研究遗传。 特发性全身性癫痫(IGE)，占40%以上 在所有的癫痫中。我们将研究三种特定形式的免疫球蛋白E： 青少年肌阵挛癫痫(JME)，癫痫伴觉醒大发作 (AGM)和癫痫伴随机大发作(RGM)。JME已经被证明是 与6号染色体的人类白细胞抗原区域有遗传关联。这个JME基因座 已被指定为EJM-1。由于JME的家族特征， 据认为，还将把其他几种形式的政府间大会联系起来 人类白细胞抗原基因座。我们在上一次拨款中验证了这一假设 句号。我们发现RGM显然与人类白细胞抗原基因座没有关联。 然而，AGM虽然在临床上不同于JME，但可能是遗传上的 一模一样。 我们在遗传学方面的进一步工作有以下四个目标 IGE： 1.为了检验在上一次拨款期间提出的假设，年度股东大会 与6号染色体上的人类白细胞抗原基因座连锁。 2.寻找引起癫痫随机发作的基因座 (RGM)，我们已经证明它在基因上与临床上不同 类似的年度股东大会和JME。 3.同时，寻找表达式中涉及的第二个位置 所有三种形式的政府间气候变化会议。 4.寻找EJM-1基因座的侧翼标记。 我们将招募通过JME、RGM和AGM患者确定的家庭； 收集所有家庭成员的血液、脑电和家族史；以及 对整个基因组中的标记物进行打字。我们将测试 AGM与人类白细胞抗原基因座的连锁，并检测所有三种形式，但尤其是 RGM，用于连接到遗传标记。我们将测试特定的候选人 与任何或所有三种形式的免疫球蛋白E连锁的基因座。 我们在上一次授予期间的发现--年度股东大会可能与EJM有关-- 1和RGM没有连锁--表明遗传连锁数据可以用来 揭开临床的异质性。他们证明了区分 不同形式的癫痫--最难解决的问题之一 研究和临床实践都可以通过搜索 疾病的遗传原因。它们还显示了对 正确的表型对常见复合体的遗传学研究至关重要 疾病。