Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation

Abstract

Autosomal dominant nocturnal frontal lobe epilepsy is a familial partial epilepsy syndrome and the first human idiopathic epilepsy known to be related to specific gene defects. Clinically available molecular genetic testing reveals mutations in three genes, CHRNA4, CHRNB2 and CHRNA2. Mutations in CHRNA4 have been found in families from different countries; the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. Clear evidence for founder effect was not reported among them, including a haplotype study carried out on the Australian and Norwegian families. Japanese and Koreans, because of their geographical closeness and historical interactions, show greater genetic similarities than do the populations of other countries where the mutation is found. Haplotype analysis in the two previously reported families showed, however, independent occurrence of the Ser284Leu mutation. The affected nucleotide was highly conserved and associated with a CpG hypermutable site, while other CHRNA4 mutations were not in mutation hot spots. Association with a CpG site accounts for independent occurrence of the Ser284Leu mutation. Journal of Human Genetics (2011) 56, 609-612; doi:10.1038/jhg.2011.69; published online 14 July 2011Keywords: acetylcholine receptor; autosomal dominant nocturnal frontal lobe epilepsy; epilepsy; founder effect; mutation INTRODUCTIONAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 118504) is a familial partial epilepsy syndrome characterised by clusters of brief frontal lobe motor seizures during drowsiness or sleep. 1,2 Seizures-often misdiagnosed as other nocturnal motor activities such as parasomnia or night terror 1-4 -vary from simple arousals to hyperkinetic activity with tonic or dystonic features. Onset usually occurs during the first two decades (mean age 10 years), but later onset has also been reported. 5 ADNFLE is the first human idiopathic epilepsy known to be related to specific gene defects. 6 Clinically available molecular genetic testing reveals mutations in three genes encoding the a4, b2 and a2 subunits of the neuronal nicotinic acetylcholine receptor (CHRNA4, CHRNB2 and CHRNA2, respectively). 7-9 Overall mutations are found in less than 20% of individuals with ADNFLE/NFLE phenotypes, suggesting their genetic heterogeneity. 10 Approximately 10-20% of patients have a positive family history and fewer than 5% a negative one. 11 Among the four mutations in CHRNA4 (Ser280Phe, Ser284Leu, Leu291dup and Thr293Ile), Ser280Phe and Ser284Leu have been identified in several unrelated families (mutation names may be different from those of previous papers; we use NP_000735.1):the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, 12-15 and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. [16][17][18][19] It has been assumed that founder effect is not relevant to ADNFLE, because most of the families studied come from different countries, 20 and a previous haplotype...

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