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 far1,2,3,4,5,6,7, 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.
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Acknowledgements
The authors thank all affected individuals and their families who participated in this study; H. Beck, F. Lehmann-Horn, J.P. Johnson and A. Ryan for discussion on the manuscript; P.C. Heinrich for support; and G. Cutting for providing the pBKRSV-hClC-2 construct. This work was supported by the German Volkswagen-Stiftung (to A.H.), the Deutsche Forschungs-Gemeinschaft (to A.H., C.F., H.L. & T.S.), the German Bundesministerium für Bildung und Forschung (to A.H. & H.L.), the Stiftung Michael (to T.S.), BONFOR (to A.H.) and the Muscular Dystrophy Association (to C.F.).
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Haug, K., Warnstedt, M., Alekov, A. et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 33, 527–532 (2003). https://doi.org/10.1038/ng1121
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DOI: https://doi.org/10.1038/ng1121
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