Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies
| Autor: | Karsten Haug, Maike Warnstedt, Alexi K. Alekov, Thomas Sander, Alfredo Ramírez, Barbara Poser, Snezana Maljevic, Simon Hebeisen, Christian Kubisch, Johannes Rebstock, Steve Horvath, Kerstin Hallmann, Joern S. Dullinger, Birgit Rau, Fritz Haverkamp, Stefan Beyenburg, Herbert Schulz, Dieter Janz, Bernd Giese, Gerhard Müller-Newen, Peter Propping, Christian E. Elger, Christoph Fahlke, Holger Lerche, Armin Heils |
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| Rok vydání: | 2003 |
| Předmět: |
Adult
Family Health Male Heterozygote DNA Complementary Microscopy Confocal Adolescent Base Sequence Reverse Transcriptase Polymerase Chain Reaction Cell Membrane DNA Mutational Analysis Molecular Sequence Data Transfection Models Biological Pedigree Electrophysiology Microscopy Fluorescence Chloride Channels Mutation Codon Terminator Genetics Humans Epilepsy Generalized Female Plasmids |
| Zdroj: | Nature Genetics. 33:527-532 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng1121 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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