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

良性成人家族性肌阵挛癫痫(BAFME)是一种常染色体显性遗传性特发性癫痫，以成人起病、高渗透率、肌阵挛、手指颤动和罕见癫痫发作为特征。BAFME仅在日本被识别。使用ABI连锁图谱集对一个日本家庭进行了连锁分析。连锁分析不排除合体2、7、8、10和17，但利用额外标记，BAFME易感基因座位于人染色体8q23-24上4.4 cM以内。我们已经分离到40多个BAC克隆，覆盖了BAFME易感区域的三分之一。我们也有横跨该地区的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。从文库中分离出最长的cDNAs克隆，发现它们与另一个基因没有同源性，也没有ORF序列。我们仍将分离这些克隆的更多5‘端区域，包含ORF。我们还在8q23-24上发现了三个不同的钾通道基因(KCNQ3、Kv8.I和Kv9.2)。由于癫痫被认为是通道病，这些基因是BAFME的候选基因。对一个日本家庭中的这三个钾通道基因进行了突变搜索。我们没有在KCNQ3和Kv8.I基因中发现任何突变，但我们在Kv8.I基因中发现了额外的5‘外显子和可能的替代3’端。Kv9.2基因也未发现突变。这三种钾通道基因启动子区域的突变搜索正在进行中。通过对其他BAFME家系进行基因分型，也排除了日本家系发生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.