Leukoencephalopathy upon disruption of the chloride channel ClC-2.

[canavan disease]

ClC-2 is a broadly expressed plasma membrane chloride channel that is modulated by voltage , cell swelling , and pH . A human mutation leading to a heterozygous loss of ClC-2 has previously been reported to be associated with epilepsy , whereas the disruption of Clcn 2 in mice led to testicular and retinal degeneration . We now show that the white matter of the brain and spinal cord of ClC-2 knock-out mice developed widespread vacuolation that progressed with age . Fluid-filled spaces appeared between myelin sheaths of the central but not the peripheral nervous system . Neuronal morphology , in contrast , seemed normal . Except for the previously reported blindness , neurological deficits were mild and included a decreased conduction velocity in neurons of the central auditory pathway . The heterozygous loss of ClC-2 had no detectable functional or morphological consequences . Neither heterozygous nor homozygous ClC-2 knock-out mice had lowered seizure thresholds . Sequencing of a large collection of human DNA and electrophysiological analysis showed that several ClC-2 sequence abnormalities previously found in patients with epilepsy most likely represent innocuous polymorphisms .