![]() ![]() (2006) did not identify pathogenic mutations in the CLCN2 gene in 61 patients with IGE or 35 patients with temporal lobe epilepsy, suggesting that CLCN2 gene mutations are not a common cause of these disorders.īy sequencing of a large collection of human DNA followed by electrophysiologic analysis, Blanz et al. On this basis, all but one of the original authors retracted the paper. (2009) found discrepancies in the family structure, phenotype, and genetic analysis. In a reevaluation of 2 of the families reported by Haug et al. In 3 of 46 unrelated families with IGE localized to 3q26 (including some of the families reported by Sander et al. (2000) identified a susceptibility locus on chromosome 3q26.1 (EIG11 607628). In a genomewide linkage study of 130 families with idiopathic generalized epilepsy (see IGE 600669), Sander et al. Immunoreactivity was also visible in astrocytic endfeet around blood vessels.Ĭontroversial Role of CLCN2 Mutations in Epilepsy Electron microscopy confirmed that CLCN2 was present in white matter astrocytes and enriched in cell processes with astrocyte-astrocyte and astrocyte-abaxonal myelin contacts. CLCN2 was not detected in neuronal perikarya. CLCN2 expression was also seen along axons, in oligodendrocytes, and in the ependymal lining. CLCN2 was enriched in perivascular astrocytes with GlialCAM ( 611642) and MLC1 ( 605908). CLCN2 showed a fine punctate quality, consistent with a membrane protein. ![]() (2013) found expression of the CLCN2 gene on the surface of cell bodies and processes of virtually all GFAP ( 137780)-positive fibrous astrocytes in the posterior limb of the internal capsule. Using immunohistochemistry of healthy human brain tissue, Depienne et al. (2003) noted that CLCN2 channels act as a chloride-efflux pathway which establishes and maintains a high transmembrane chloride gradient necessary for an inhibitory GABA response. Localization was within or adjacent to active zones of symmetrical, presumed GABAergic, synapses, and the authors concluded that CLCN2 is involved in transmembrane chloride movements associated with GABAergic synaptic transmission. In addition, the end feet of astrocytes in the neuropil and around small blood vessels were strongly immunoreactive. (2000) showed that CLCN2 channels were localized in the plasma membranes of dendrites, axons, and somata of pyramidal and nonpyramidal cells of the hippocampus. The chloride homeostasis of neurons and nonneuronal cells is maintained in part by chloride conductance through the CLCN2 channel. Compounds that exploit the pH mechanism of activating endogenous CLC2 channels may provide a pharmacologic option for increasing chloride conductance in airways of CF patients. Acidic extracellular pH increased chloride-36 efflux rates in both cell types, although the CLC2-overexpressing cells had significantly greater chloride conduction and a longer duration of efflux than the parental cells. To determine whether changes in the extracellular pH alone could initiate chloride transport via CLC2 channels, they performed chloride-36 efflux studies on overexpressing cells and cells with endogenous expression of CLC2. CF cells stably transfected with the antisense CLC2 cDNA showed reduced expression of CLC2 compared with parental cells by Western blotting, and a significant reduction in the magnitude of pH-dependent HACCs. ![]() Reduction of extracellular pH to 5.0 caused significant increases in HACCs in overexpressing cells and the appearance of robust currents in parental cells from the cystic fibrosis patient. Whole-cell patch-clamp analysis of cells overexpressing CLC2 identified hyperpolarization-activated chloride ion currents (HACCs) that displayed time- and voltage-dependent activation and an inwardly rectifying steady-state current voltage relationship. The explore this possibility, they manipulated genetically the expression levels of CLC2 channels in airway epithelial cells derived from cystic fibrosis patients. (1998) found that CLC2 chloride channels are expressed in epithelia affected by cystic fibrosis (CF 219700) and raised the possibility that these might represent an alternative target for pharmacotherapy of CF. ![]()
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