Identification and cell biological analysis of the gene for benign adult familial myoclonic epilepsy

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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. Chromosome 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 also found three different potassium channel genes (KCNQ3, Kv8.1 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 Kv8.1 gene, but we found an extra 5' exon and possible alternative 3' end in the Kv8.1 gene. No mutation was found in the Kv9.2 gene either. Analysis of promoter activity was performed by using luciferase assay to determine possible promoter region of these potassium channel genes, resulted in the finding of new essential elements in these promoters. The possibility of founder effect in Japanese families is also excluded by genotyping of the other families with BAFME.