Leukoencephalopathy upon disruption of the chloride channel ClC-2
Leukoencephalopathy upon disruption of the chloride channel ClC-2
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DOI：
10.1523/jneurosci.0338-07.2007
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发表时间：
2007-06-13
影响因子：
5.3
通讯作者：
Jentsch, Thomas J.
中科院分区：
文献类型：
--
作者：
Blanz, Judith;Schweizer, Michaela;Jentsch, Thomas J.
ClC-2是一种广泛表达的质膜氯离子通道，受电压、细胞肿胀和pH调节。导致ClC-2杂合丢失的人类突变先前已被报道与癫痫相关，而小鼠中Clcn 2的破坏导致睾丸和视网膜变性。我们现在表明，C1 C-2基因敲除小鼠的脑和脊髓的白色物质随着年龄的增长而发生广泛的空泡化。充满液体的空间之间出现髓鞘的中央，但不是周围神经系统。相比之下，神经元形态似乎正常。除先前报告的失明外，神经功能缺损为轻度，包括中枢听觉通路神经元传导速度降低。ClC-2的杂合丢失没有可检测的功能或形态学后果。无论是杂合子还是纯合子ClC-2基因敲除小鼠都没有降低癫痫发作阈值。对大量人类DNA的测序和电生理分析表明，以前在癫痫患者中发现的几种ClC-2序列异常很可能代表无害的多态性。
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.