Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy
| Autor: | Holger Lerche, Georgeta Teodorescu, Cécile Saint-Martin, Eric LeGuern, Gregory Gauvain, Jean Christophe Poncer, Christoph Fahlke, Jennie Garcia-Olivares, Isabelle Gourfinkel-An, Rima Nabbout, Yvonne G. Weber, Snezana Maljevic, Christel Depienne, Estelle Fedirko, Jan-Peter Ernst |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Patch-Clamp Techniques Adolescent DNA Mutational Analysis Molecular Sequence Data Mutation Missense medicine.disease_cause Transfection Cell Line Membrane Potentials Idiopathic generalized epilepsy Epilepsy Young Adult Chloride Channels Genetics medicine Missense mutation Humans Amino Acid Sequence Genetics (clinical) Loss function CLCN2 Family Health Mutation biology Sequence Homology Amino Acid Middle Aged medicine.disease Phenotype Pedigree CLC-2 Chloride Channels Chloride channel biology.protein Epilepsy Generalized Female |
| Zdroj: | Human mutation. 30(3) |
| ISSN: | 1098-1004 |
| Popis: | 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 in- volvement 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. Hum Mutat 30, 397-405, 2009. & 2009 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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