title: Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy.
abstract: Heterozygous mutations in the CLCN2 gene encoding the voltage-gated chloride channel CLC2 have been identified in patients with idiopathic generalized epilepsy (IGE). Yet the involvement of CLCN2 in epilepsy remains controversial. To investigate the involvement of CLCN2 in another independent sample, we screened 52 unrelated patients from IGE families and 23 patients with Doose syndrome for mutations in CLCN2. No mutations were found in patients with Doose syndrome. In three unrelated IGE families, we identified two novel missense mutations, p.Arg235Gln and p.Arg577Gln, which were absent in large ethnically-matched control populations, and one novel p.Arg644Cys variant, which was also found in five Indian controls. Functional characterization of mutant channels using heterologous expression in mammalian cells and whole-cell patch-clamp recordings revealed faster deactivation kinetics as the major phenotype of both missense mutations. This finding predicts a loss of function that may contribute to intracellular chloride accumulation or neuronal hyperexcitability. However, the incomplete segregation of the mutations among affected members and the transmission by unaffected parents suggests that these CLCN2 mutations alone are not sufficient to induce epilepsy. They may instead represent susceptibility factors among other so far undetected genetic alterations in the respective families.
authors.affiliation: INSERM, U679 Neurologie et Thérapeutique Expérimentale, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Saint-Martin
authors.forename: Grégory
authors.initials: G
authors.lastname: Gauvain
authors.forename: Georgeta
authors.initials: G
authors.lastname: Teodorescu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourfinkel-An
authors.forename: Estelle
authors.initials: E
authors.lastname: Fedirko
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Ernst
authors.forename: Jennie
authors.initials: J
authors.lastname: Garcia-Olivares
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Poncer
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000090007:CLC-2 Chloride Channels; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D055815:Young Adult
chemical_list: D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels