title: Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.
abstract: Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Bonn, Wilhelmstr. 31, 53111 Bonn, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Haug
authors.forename: Maike
authors.initials: M
authors.lastname: Warnstedt
authors.forename: Alexi K
authors.initials: AK
authors.lastname: Alekov
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramírez
authors.forename: Barbara
authors.initials: B
authors.lastname: Poser
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Simon
authors.initials: S
authors.lastname: Hebeisen
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Johannes
authors.initials: J
authors.lastname: Rebstock
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hallmann
authors.forename: Joern S
authors.initials: JS
authors.lastname: Dullinger
authors.forename: Birgit
authors.initials: B
authors.lastname: Rau
authors.forename: Fritz
authors.initials: F
authors.lastname: Haverkamp
authors.forename: Stefan
authors.initials: S
authors.lastname: Beyenburg
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Dieter
authors.initials: D
authors.lastname: Janz
authors.forename: Bernd
authors.initials: B
authors.lastname: Giese
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Armin
authors.initials: A
authors.lastname: Heils
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000235:genetics*; D018388:Codon, Terminator; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D004829:Epilepsy, Generalized / Q000235:genetics*; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010957:Plasmids / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D018118:Chloride Channels; D018388:Codon, Terminator; D018076:DNA, Complementary