Linkage and mutational analysis of CLCN2 in childhood absence epilepsy

Abstract

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score = 2.3, p<0.009; HLOD = 1.5, α = 0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT  2(1) = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele:  2(1) = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11, and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.

ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion

“…Over the past years, several mutations in the gene encoding for ClC-2 have been described (Stogmann et al, 2006;Everett et al, 2007;Combi et al, 2009;Saint-Martin et al, 2009); however, the study by Haug et al (2009), which established the link between mutations in CLCN2 and epilepsy, has recently been retracted. Moreover, mutations found in humans do not lead to drastic changes in biophysical properties of ClC-2 (Blanz et al, 2007), as one might expect for a single disease-causing gene.…”

“…However, the disruption of ClC-2 in mice did not entail epilepsy Nehrke et al, 2002;Blanz et al, 2007). This has been controversial, because mutations in the gene encoding ClC-2 in humans have been linked to epilepsy (D'Agostino et al, 2004;Everett et al, 2007).…”

Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

“…No human disease has been unequivocally related to mutations in CLCN2, the gene encoding ClC-2. Heterozygous mutations in CLCN2 were described as a cause of idiopathic generalised epilepsies, [11][12][13][14][15][16][17] but this fi nding was later refuted 1,18 and the original paper was retracted. 17 Because mutant mice without functional ClC-2 have a leukoencephalopathy with intramyelinic oedema, 5,6,19 ClC-2 was proposed to have a role in brain ion and water homoeostasis; 5,6 however, this hypothesis has not been confi rmed in human beings.…”

Clcn2encodes the hyperpolarization-activated chloride channel in the ducts of mouse salivary glands

“…Analysis of genetic diseases in humans and of the phenotype of Clcn2 null mice suggests important physiological roles for ClC-2 in several different tissues. Human mutations in the gene encoding ClC-2 (CLCN2) have been linked to epilepsy (3,18,20), whereas Clcn2 Ϫ/Ϫ mice develop severe degradation of the retina and the testis (6,35). It has been hypothesized that disruption of ClC-2 expression impairs transepithelial transport of the blood-organ barrier, and this change in the environment of photoreceptors and spermatocytes leads to cell death and ultimately to blindness and infertility (6).…”