Identification and molecular cloning of the gene for benign adult familial myoclonic epilepsy.

良性成人家族性肌阵挛性癫痫（Benignadulfamilialmyoclonicepilepsy，BAFME）是一种常染色体显性遗传的特发性癫痫，以成人发病、高穿透率、肌阵挛、手指震颤和罕见癫痫发作为特征。利用ABI连锁图谱集对一个日本家系进行了连锁分析。染色体2、7、8、10和17号染色体的连锁分析未排除染色体2、7、8、10和17号染色体，但利用额外标记的分析结果表明，BAFME易感位点位于染色体8 q23 -24上的4.4cM范围内。我们已经分离出超过40个BAC克隆，覆盖了三分之一的BAFME易感区域。我们也有跨越该区域的YAC重叠群。利用这些BAC和YAC克隆进行外显子捕获，分离出两个新的外显子序列。从cDNA文库中分离出最长的cDNA克隆，发现它们与另一个基因既无同源性，也无ORF。我们还将分离这些克隆的更多5'区，包含ORF。我们还在8 q23 - 24上发现了三个不同的钾通道基因（KCNQ 3、Kv8.1和Kv9.2）。由于癫痫被认为是通道病，因此它们是BAFME的候选基因。在一个日本家族中对这三个钾通道基因进行突变搜索。在KCNQ 3和Kv8.I基因中均未发现突变，但在Kv8.I基因中发现了一个额外的5'外显子和可能的替代3'末端。Kv9.2基因也未发现突变。这三个钾离子通道基因启动子区的突变搜索正在进行中。通过对其他BAFME家系进行基因分型，也排除了日本家系中创始人效应的可能性。

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant idiopathic epilepsy characterized by adult-onset, high penetration rate, myoclonus, tremulous finger movement and infrequent epileptic seizure. BAFME was recognized only in Japan.Linkage analysis was carried out in a Japanese family using ABI Linkage Map Set. Chyomosome 2, 7, 8, 10 and 17 were not excluded by linkage analysis, but it was strongly suggested that BAFME susceptibility locus is within 4.4cM on the human chromosome 8q23-24 by using extra markers. We have isolated more than 40 BAC clones covering one third of BAFME susceptibility region. We also had YAC contig spanning this region. By using these BAC and YAC clones, exon trapping was performed, resulted in the isolation of two novel exonic sequences. The isolation of the longest cDNAS clone from cDNA library revealed that they have neither homology with the other gene, nor ORF in their sequences. We are still going to isolate more 5' region of these clones, containing ORF. We also found three different potassium channel genes (KCNQ3, Kv8.I and Kv9.2) on 8q23-24.Because epilepsies are thought to be channelopathy, these are candidate genes for BAFME. Mutation search was performed on these three potassium channel genes in a Japanese family. We couldn't find any mutation both in the KCNQ3 and Kv8.I gene, but we found an extra 5' exon and possible alternative 3' end in the Kv8.I gene. No mutation was found in the Kv9.2 gene either. Mutation search in the promoter region of these three potassium channel gene are in progress. The possibility of founder effect in Japanese families is also excluded by genotyping of the other families with BAFME.