Neuronal nicotinic receptors in human epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare monog enic idiopathic partial epilepsy characterized by clusters of frontal lobe motor seizures during sleep. Recently, it has been shown that mutations of the chromosome-20q-located neuronal nicotinic acetylcholine receptor alpha 4-subunit (CHRNA4) are associated with ADNFLE in some families, but that ot her families are not linked to this locus. Both CHRNA4 mutations (Ser248Phe and 776ins3) identified so far are found in the pore-forming second transm embrane region of the gene. Electrophysiological studies showed that mutati ons in this functional important part of the receptor subunit have a profou nd effect on the permeability for calcium ions. Interestingly, the Ser248Ph e mutation was found again in a second ADNFLE family. Haplotype analysis ex cluded a founder effect and showed that Ser248Phe occurred independently tw ice. This provides the possibility to study the effect of the same mutation on different genetic backgrounds. Several attempts have been made to ident ify additional genes responsible for ADNFLE. But despite some positive link age results including the CHRNA3-CHRNA5-CHRNB2 cluster on chromosome 15q24, no further mutations have been found so far. The mutation screening of fun ctionally important parts of CHRNA5 in 12 ADNFLE patients did not support a causative role of this nicotinic acetylcholine receptor subunit. (C) 2000 Elsevier Science B.V. All rights reserved.