Leukoencephalopathy upon disruption of the chloride channel ClC-2.
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 Clcn2 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.
Blanz
Judith
J
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, D-20252 Hamburg, Germany.
Schweizer
Michaela
M
Auberson
Muriel
M
Maier
Hannes
H
Muenscher
Adrian
A
Hübner
Christian A
CA
Jentsch
Thomas J
TJ
D000367:Age Factors; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D001927:Brain Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000090007:CLC-2 Chloride Channels; D017825:Canavan Disease / Q000473:pathology; D018118:Chloride Channels / Q000172:deficiency / Q000502:physiology*; D003711:Demyelinating Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation; D009186:Myelin Sheath / Q000473:pathology / Q000648:ultrastructure; D018075:RNA, Complementary / Q000008:administration & dosage; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D014617:Vacuoles / Q000473:pathology / Q000648:ultrastructure
D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; C000715428:Clcn2 protein, mouse; D018075:RNA, Complementary; D018698:Glutamic Acid