De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.
De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.
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DOI：
10.1038/srep15199
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发表时间：
2015-10-19
影响因子：
4.6
通讯作者：
Matsumoto N
中科院分区：
文献类型：
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作者：
Saitsu H;Akita T;Tohyama J;Goldberg-Stern H;Kobayashi Y;Cohen R;Kato M;Ohba C;Miyatake S;Tsurusaki Y;Nakashima M;Miyake N;Fukuda A;Matsumoto N
由KCNB1编码的电压门控Kv2.1钾通道在锥体神经元中产生主要的延迟整流钾电流。最近，在三名癫痫性脑病患者和一名神经发育障碍患者中发现了从头杂合错义KCNB1突变。然而，婴儿癫痫患者KCNB1突变的频率及其对神经元活动的影响尚不清楚。我们检索了总共437例婴儿癫痫患者的全外显子组测序数据，在2例表现为精神发育迟缓和严重婴儿全身性癫痫发作伴高振幅棘波脑电图放电的患者中发现了新的从头杂合错义KCNB1突变。位于通道电压传感器（p.R306C）中的突变破坏了传感器的灵敏度和协同性，而通道孔结构域（p.G401R）中的突变选择性地消除转染的锥体神经元中的内源性Kv2电流，表明显性负效应。这两种突变体通过阻止深峰间电压的产生来抑制神经元的重复放电。因此，KCNB1突变可能是婴儿癫痫的罕见遗传原因，锥体神经元放电不足会干扰神经元回路的发育和稳定性，导致疾病表型。
The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons. Recently, de novo heterozygous missense KCNB1 mutations have been identified in three patients with epileptic encephalopathy and a patient with neurodevelopmental disorder. However, the frequency of KCNB1 mutations in infantile epileptic patients and their effects on neuronal activity are yet unknown. We searched whole exome sequencing data of a total of 437 patients with infantile epilepsy, and found novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges. The mutation located in the channel voltage sensor (p.R306C) disrupted sensitivity and cooperativity of the sensor, while the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect. Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages. Thus KCNB1 mutations can be a rare genetic cause of infantile epilepsy, and insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes.