A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy

Objective: To identify the mutation responsible for autosomal dominant noct urnal frontal lobe epilepsy (ADNFLE) in a nonwhite family. Background: ADNF LE is newly recognized as an entity of idiopathic partial epilepsy. Recentl y, two different mutations of the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) gene were identified in a white family as a cause of ADNFLE, Methods: Four affected and three unaffected individuals in thre e generations of a Japanese family with ADNFLE, and 100 unrelated healthy J apanese volunteers were studied. Clinical features and EEG findings in affe cted individuals were consistent with those of ADNFLE reported in white fam ilies with ADNFLE. Mutations within the CHRNA4 gene were screened for using single-strand conformation polymorphism analysis (SSCA) and were determine d by direct sequencing. The mutation identified was sought in volunteers by the amplification refractory mutation system. Results: A C-to-T exchange ( C755T) was found in exon 5 of the CHRNA4 gene on one allele of affected ind ividuals. C755T segregated in affected individuals and was not found in 200 alleles obtained from the volunteers. C755T replaced serine 252 (Ser(252)) in the second membrane-spanning domain (M2) of CHRNA4 with a leucine. Ser( 252) is conserved characteristically in the alpha-subunit of acetylcholine receptor and is considered to play an important role in channel function. C onclusion: C755T is a novel missense mutation of the CHRNA4 gene causing au tosomal dominant nocturnal frontal lobe epilepsy in this Japanese family.