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的分子表征迄今为止还没有成功。这可能部分是由于这种疾病中存在的遗传和临床异质性。家族性成人肌阵挛性癫痫（familial adult myoclonic epilepsy，FAME）是一种罕见的特发性全身性癫痫，其特征为常染色体显性遗传、成人起病、不同程度的肢体肌阵挛、罕见的强直-阵挛性发作和良性病程。我们最近定位了这种疾病的基因染色体8q24.1。这项研究的目的是确定基因负责FAME和表征蛋白质的作用，这种疾病的具体和神经兴奋性更普遍。这一目标将通过几种并行方法来实现。首先，使用细菌人工染色体和cosplay定位克隆对应于FAME基因座的区域。其次，将在整个地区检查新的多态性标记，以确定我们的FAME家族之间的共享单倍型。最后，将检查通过EST数据库或通过筛选cDNA文库鉴定的推定cDNA的突变。在鉴定FAME基因后，将进行适当的细胞、生物化学和生理学研究以表征FAME蛋白的功能。然后可以建立FAME的小鼠模型，并将允许体内发病机制的研究。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.