Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.
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.
Haug
Karsten
K
Institut für Humangenetik, Universitätsklinikum Bonn, Wilhelmstr. 31, 53111 Bonn, Germany.
Warnstedt
Maike
M
Alekov
Alexi K
AK
Sander
Thomas
T
Ramírez
Alfredo
A
Poser
Barbara
B
Maljevic
Snezana
S
Hebeisen
Simon
S
Kubisch
Christian
C
Rebstock
Johannes
J
Horvath
Steve
S
Hallmann
Kerstin
K
Dullinger
Joern S
JS
Rau
Birgit
B
Haverkamp
Fritz
F
Beyenburg
Stefan
S
Schulz
Herbert
H
Janz
Dieter
D
Giese
Bernd
B
Müller-Newen
Gerhard
G
Propping
Peter
P
Elger
Christian E
CE
Fahlke
Christoph
C
Lerche
Holger
H
Heils
Armin
A
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
D018118:Chloride Channels; D018388:Codon, Terminator; D018076:DNA, Complementary