Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel
Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel
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DOI：
10.1073/pnas.211431298
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发表时间：
2001-10-09
影响因子：
11.1
通讯作者：
Steinlein, OK
中科院分区：
文献类型：
--
作者：
Dedek, K;Kunath, B;Steinlein, OK
KCNQ2和KCNQ3是两个同源的K+通道亚基，它们可以结合形成具有神经元M通道特性的异构体通道。任何一个亚单位的功能丧失突变都可能导致良性家族性新生儿惊厥(BFNC)，这是一种新生儿的全身性特发性癫痫。我们现在描述一种综合征，在这种综合征中，BFNC在晚年之后会出现肌痉挛，即骨骼肌的非自愿收缩。所有受影响的myokymia/BFNC家族成员都携带一个突变(R207W)，该突变中和了KCNQ2的S4电压传感器片段中的一个带电氨基酸。这种替换导致了KCNQ2的电压依赖性激活的移位，以及去极化时激活的显著减慢。肌萎缩症被认为是下运动神经元过度兴奋的结果，事实上，KCNQ2和KCNQ3mRNAs都在脊髓前角检测到，在那里出现了下运动神经元的细胞。我们认为，运动神经元和中枢神经元之间的放电模式的差异，再加上R207W突变体的电压激活急剧放缓，解释了为什么这个特定的KCNQ2突变体除了BFNC外还会导致肌痉挛。
KCNQ2 and KCNQ3 are two homologous K+ channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.