Other entities represented in this entry:
ORPHA: 307; DO: 0111312;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.1 | {Epilepsy, juvenile absence, susceptibility to, 2} | 607628 | Autosomal dominant | 3 | CLCN2 | 600570 |
| 3q27.1 | {Epilepsy, juvenile myoclonic, susceptibility to, 8} | 607628 | Autosomal dominant | 3 | CLCN2 | 600570 |
| 3q27.1 | {Epilepsy, idiopathic generalized, susceptibility to, 11} | 607628 | Autosomal dominant | 3 | CLCN2 | 600570 |
A number sign (#) is used with this entry because some evidence has suggested that susceptibility to idiopathic generalized epilepsy-11 (EIG11), juvenile myoclonic epilepsy-8 (EJM8), and juvenile absence epilepsy-2 (EJA2) may be conferred by variation in the chloride channel-2 gene (CLCN2; 600570) on chromosome 3q27. However, there has been some controversy over whether variation in the CLCN2 gene has a role in epilepsy (see MOLECULAR GENETICS).
Both juvenile myoclonic epilepsy and juvenile absence epilepsy are subtypes of idiopathic generalized epilepsy (EIG).
For a general phenotypic description and a discussion of genetic heterogeneity of these disorders, see EIG1 (600669), EJM1 (254770), and EJA1 (607631).
Sander et al. (2000) used nonparametric multipoint linkage analysis to identify susceptibility loci among 130 IGE-multiplex families ascertained through a proband with childhood or juvenile absence epilepsy or juvenile myoclonic epilepsy, and 1 or more sibs affected by an IGE trait. They obtained evidence for a novel IGE susceptibility locus on chromosome 3q26 with a peak nonparametric linkage (NPL) score of 4.19 at D3S3725 (p = 0.000017).
In 2 sibs with juvenile absence epilepsy found by Sander et al. (2000) to be linked to chromosome 3q26, Haug et al. (2003) identified a heterozygous mutation in the CLCN2 gene (G715E; 600570.0003). Another sib with generalized spike-wave discharges on EEG also carried the mutation. The father, who also carried the mutation, reportedly had unclassified seizures in childhood, but his severe alcoholism as an adult rendered his disease status uncertain. Functional studies of the mutant channel showed normal current amplitudes, but altered voltage-dependent gating, potentially leading to hyperexcitability. The family structure, diagnosis, and mutation status were confirmed by Kleefuss-Lie et al. (2009). The mutation was not observed in 4,700 German control individuals.
In 3 of 46 unrelated families with IGE localized to 3q26 (including some of the families reported by Sander et al. (2000)), Haug et al. (2003) identified 3 mutations in the CLCN2 gene (600570.0001-600570.0003). In a reevaluation of 2 of the families, 1 with juvenile myoclonic epilepsy and 1 with childhood absence epilepsy Haug et al. (2003), Kleefuss-Lie et al. (2009) found discrepancies in the family structure, phenotype, and genetic analysis. On this basis, all but one of the original authors retracted the paper.
Niemeyer et al. (2010) disagreed with the conclusion by Kleefuss-Lie et al. (2009) that some of the work by Haug et al. (2003) had merit. Based on lack of functional consequences of the variants reported by Haug et al. (2003) (600570.0001-600570.0003), Niemeyer et al. (2010) asserted that there is no evidence for a role of CLCN2 variants in idiopathic generalized epilepsy.
In 2 sibs of Tunisian origin with juvenile myoclonic epilepsy, Saint-Martin et al. (2009) identified a heterozygous mutation in the CLCN2 gene (R235Q; 600570.0004). Another sib with JME was not available for genetic analysis. The mutation was not observed in 263 control individuals from North Africa or 183 French controls. Saint-Martin et al. (2009) identified a different heterozygous mutation in the CLCN2 gene (R577Q; 600570.0005) in 2 German sibs with idiopathic generalized epilepsy. The mutation was not observed in 203 German controls or 183 French controls. In both families, the unaffected father also had the mutation, suggesting either reduced penetrance or that additional unidentified factors are necessary for full phenotypic expression.
'ECA3' was previously used to designate the locus on 3q26 for childhood absence epilepsy; this had since been removed since the paper was retracted (Haug et al., 2003).
Haug, K., Warnstedt, M., Alekov, A. K., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., and 13 others. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nature Genet. 33: 527-532, 2003. Note: Retraction: Nature Genet. 41: 1043 only, 2009. [PubMed: 12612585] [Full Text: https://doi.org/10.1038/ng1121]
Kleefuss-Lie, A., Friedl, W., Cichon, S., Haug, K., Warnstedt, M., Alekov, A., Sander, T., Ramirez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., and 15 others. CLCN2 variants in idiopathic generalized epilepsy. (Letter) Nature Genet. 41: 954-955, 2009. [PubMed: 19710712] [Full Text: https://doi.org/10.1038/ng0909-954]
Niemeyer, M. I., Cid, L. P., Sepulveda, F. V., Blanz, J., Auberson, M., Jentsch, T. J. No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. (Letter) Nature Genet. 42: 3 only, 2010. [PubMed: 20037607] [Full Text: https://doi.org/10.1038/ng0110-3]
Saint-Martin, C., Gauvain, G., Teodorescu, G., Gourfinkel-An, I., Fedirko, E., Weber, Y. G., Maljevic, S., Ernst, J.-P., Garcia-Olivares, J., Fahlke, C., Nabbout, R., LeGuern, E., Lerche, H., Poncer, J. C., Depienne, C. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Hum. Mutat. 30: 397-405, 2009. [PubMed: 19191339] [Full Text: https://doi.org/10.1002/humu.20876]
Sander, T., Schulz, H., Saar, K., Gennaro, E., Riggio, M. C., Bianchi, A., Zara, F., Luna, D., Bulteau, C., Kaminska, A., Ville, D., Cieuta, C., and 14 others. Genome search for susceptibility loci of common idiopathic generalised epilepsies. Hum. Molec. Genet. 9: 1465-1472, 2000. [PubMed: 10888596] [Full Text: https://doi.org/10.1093/hmg/9.10.1465]