CLCN2 – Idiopathic Generalized Epilepsy

CLCN2 encodes the voltage-gated chloride channel ClC-2, which has been proposed to regulate neuronal excitability through GABAergic and astrocytic mechanisms (PMID:15021241). Initial screens report that CLCN2 mutations are rare in idiopathic generalized epilepsy (IGE): in one cohort of 80 patients, three pathogenic or likely pathogenic variants were identified (PMID:33528079), whereas a screen of 96 genetically predisposed patients found no definitively pathogenic alleles (PMID:16932951). Additional sequencing in IGE families revealed two missense variants with faster channel deactivation but incomplete segregation among affected members (PMID:19191339).

Functional studies of CLCN2 variants demonstrate a loss-of-function mechanism consistent with haploinsufficiency. The frameshift mutation c.597dup (p.Met200fs) yields a non-functional channel that fails to traffic to the plasma membrane, and the missense variant c.2144G>A (p.Gly715Glu) shows gating properties indistinguishable from wild type, suggesting variant-specific effects (PMID:15252188). Real-time PCR quantification reveals a ~50% reduction in CLCN2 transcript levels in epilepsy-associated brain tissue, implicating altered gene expression even in the absence of coding mutations (PMID:17156979).

Overall, the association between CLCN2 and IGE is supported by rare case observations and in vitro functional concordance but lacks reproducible segregation and prevalence data. Genetic testing for CLCN2 may be considered for research and differential diagnosis in select IGE cases, though its routine clinical utility remains limited at present.

References

• Current opinion in neurology • 2004 • Genetics of the epilepsies. PMID:15021241
• Internal medicine journal • 2022 • Customised targeted massively parallel sequencing enables more precise diagnosis of patients with epilepsy. PMID:33528079
• Neurogenetics • 2006 • Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes. PMID:16932951
• Physiological genomics • 2004 • Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies. PMID:15252188
• Biochimica et biophysica acta • 2007 • Quantification of chloride channel 2 (CLCN2) gene isoforms in normal versus lesion- and epilepsy-associated brain tissue. PMID:17156979
• Human mutation • 2009 • Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. PMID:19191339

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