The molecular and genetic basis of myoclonic epilepsy

描述（由申请人提供）：青少年肌阵挛性癫痫（JME）是最常见的儿童癫痫之一。尽管认识到强大的遗传因素，JME的分子表征迄今尚未成功。这可能部分是由于这种疾病存在遗传和临床异质性。家族性成人肌阵挛性癫痫（FAME）是一种罕见的特发性全身性癫痫，其特点是常染色体显性遗传，成人发病，四肢有不同程度的肌阵挛，罕见的强直-阵挛性发作，病程良性。我们最近在8q24.1号染色体上定位了这种疾病的一个基因。本研究的目的是确定负责FAME的基因，并确定该蛋白在这种疾病中的作用，以及更普遍的神经兴奋性。这一目标将使用几个并发方法来实现。首先，利用细菌人工染色体和子体对FAME基因座对应的区域进行定位克隆。其次，将在整个区域检测新的多态性标记，以确定我们FAME家族之间共享的单倍型。最后，通过EST数据库或筛选cDNA文库鉴定的推定cDNA将被检测突变。在确定FAME基因后，将进行适当的细胞、生化和生理学研究，以表征FAME蛋白的功能。然后可以创建FAME的小鼠模型，并将允许在体内研究发病机制。这些实验将在专门针对这种性质的实验的分子遗传学实验室中进行。

DESCRIPTION (provided by applicant): Juvenile myoclonic epilepsy (JME) is among the commonest of the childhood epilepsies. Despite the recognition of strong genetic factors, molecular characterization of JME has thus far been unsuccessful. This may be due, in part, to genetic and clinical heterogeneity that is present in this disorder. Familial adult myoclonic epilepsy (FAME) is a rare idiopathic generalized epilepsy characterized by autosomal dominant inheritance, adult onset, varying degrees of myoclonus in the limbs, rare tonic-clonic seizures and a benign course. We have recently localized a gene for this disorder to chromosome 8q24.1. The objective of this research is to identify the gene responsible for FAME and to characterize the protein's role in this disorder specifically and in neuroexcitability more generally. This objective will be attained using several concurrent methods. First, the region corresponding to the FAME locus is being positionally cloned using bacterial artificial chromosomes and cosmids. Secondly, new polymorphic markers will be examined across the region to identify a shared haplotype between our FAME families. Finally, putative cDNAs identified through the EST database or through screening cDNA libraries, will be examined for mutations. Upon the identification of the FAME gene, appropriate cellular, biochemical, and physiological investigations will be performed to characterize the function of the FAME protein. Mouse models of FAME can then be created and will allow investigations of pathogenesis in vivo. These experiments will take place in a molecular genetics laboratory geared specifically towards experiments of this nature.