The molecular and genetic basis of myoclonic epilepsy

描述(申请人提供)：青少年肌阵挛癫痫(JME)是最常见的儿童癫痫之一。尽管人们认识到了很强的遗传因素，但JME的分子表征迄今并不成功。这可能部分归因于这种疾病中存在的遗传和临床异质性。家族性成人肌阵挛癫痫(MAME)是一种罕见的特发性全身性癫痫，以常染色体显性遗传、成人起病、四肢不同程度的肌阵挛、罕见的强直-阵挛发作和良性病程为特征。我们最近将这种疾病的一个基因定位在染色体8q24.1。这项研究的目的是确定与FAME有关的基因，并明确这种蛋白质在这种疾病中的作用，以及更广泛地在神经兴奋性中的作用。这一目标将使用几种同时进行的方法来实现。首先，与FAME基因座对应的区域正在使用细菌人工染色体和宇宙染色体进行定位克隆。其次，将在整个地区检查新的多态标记，以确定我们名气家族之间共享的单倍型。最后，通过EST数据库或筛选cDNA文库确定的假定cDNA将被检查突变。在鉴定FAME基因后，将进行适当的细胞、生化和生理研究，以确定FAME蛋白的功能。然后可以建立FAME的小鼠模型，并将允许研究体内的发病机制。这些实验将在一个专门针对这种性质的实验的分子遗传学实验室进行。

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.