title: Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore.
abstract: Certain mutations in specific parts of the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4, CHRNB2, and probably CHRNA2, can cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). All but one of the known causative mutations are located in the second transmembrane region (TM2), which serves as the major ion poreforming domain of the receptor. Functional characterization of these ADNFLE mutations has shown that although each mutant exhibits specific properties, they all confer a gain of function with increased sensitivity to acetylcholine. In this work, we characterize the second and third ADNFLE-associated mutations that are external to TM2 but affect different amino acid residues within the third transmembrane region (TM3). The two new CHRNB2 mutations were identified in three families of Turkish Cypriot, Scottish, and English origin. These TM3 mutations elicit the same gain of function pathomechanism as observed for the TM2 mutations with enhanced acetylcholine sensitivity, despite their unusual localization within the gene. Electrophysiological experiments, including single channel measurements, revealed that incorporation of these new mutant subunits does not affect the conductance of the ionic pore but increases the probability of opening. Determination of the sensitivity to nicotine for nAChRs carrying mutations in TM2 and TM3 showed clear differences in the direction and the extent to which the window current for nicotine sensitivity was shifted for individual mutations, indicating differences in pharmacogenomic properties that are not readily correlated with increased ACh affinity.
authors.affiliation: Department of Neuroscience, University of Geneva, CMU, 1, rue M. Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Hoda
authors.forename: Wenli
authors.initials: W
authors.lastname: Gu
authors.forename: Marc
authors.initials: M
authors.lastname: Friedli
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Phillips
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: David
authors.initials: D
authors.lastname: Goudie
authors.forename: Richard
authors.initials: R
authors.lastname: Roberts
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Jayesh
authors.initials: J
authors.lastname: Patel
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Ortrud K
authors.initials: OK
authors.lastname: Steinlein
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D017034:Epilepsy, Frontal Lobe / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D009154:Mutation; D018408:Patch-Clamp Techniques; D010597:Pharmacogenetics / Q000379:methods; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000927:Anticonvulsants; D007473:Ion Channels; D021122:Protein Subunits; D011978:Receptors, Nicotinic