Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy.
Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy.
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进行性肌阵癫痫KCNC1变体引起发育性树突病。
DOI：
10.1111/epi.16867
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发表时间：
2021-05
期刊：
影响因子：
5.6
通讯作者：
Schorge S
中科院分区：
文献类型：
--
作者：
Carpenter JC;Männikkö R;Heffner C;Heneine J;Sampedro-Castañeda M;Lignani G;Schorge S
KCNC1 突变可导致严重的神经功能障碍，包括智力障碍、癫痫和共济失调。 Arg320His 变异发生在通道的电压感应域中，会导致一种高度渗透性和特定形式的进行性肌阵挛癫痫伴严重共济失调，称为钾通道突变 (MEAK) 所致的肌阵挛癫痫和共济失调。 KCNC1 编码电压门控钾通道 KV3.1，该通道对于实现中间神经元的高频放电非常重要，这增加了 MEAK 与中间神经元功能降低相关的可能性。为了确定该变体如何触发 MEAK，我们在体外皮质中间神经元中表达 KV3.1bR320H，并研究其对神经元功能和形态的影响。我们还对表达 KV3.1b 的卵母细胞进行了电生理记录，以确定突变是否引入了门控孔电流。 KV3.1bR320H 变体的表达极大地降低了成熟皮质中间神经元的兴奋性，并且表达这些通道的细胞无法支持高频放电。突变通道还对形态产生意想不到的影响，严重损害神经突发育和中间神经元活力，这种影响无法通过阻断 KV3 通道来挽救。卵母细胞记录证实，在成人 KV3.1b 亚型中，R320H 通过减缓通道激活而产生显性负功能丧失效应，但不会引入潜在有毒的门控孔电流。总的来说，我们的数据表明，除了高频放电的调节之外，KV3.1 通道在神经元发育中发挥着迄今为止未被认识的作用。 MEAK 可被描述为一种发育性树突病。
Mutations in KCNC1 can cause severe neurological dysfunction, including intellectual disability, epilepsy, and ataxia. The Arg320His variant, which occurs in the voltage‐sensing domain of the channel, causes a highly penetrant and specific form of progressive myoclonus epilepsy with severe ataxia, designated myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). KCNC1 encodes the voltage‐gated potassium channel KV3.1, a channel that is important for enabling high‐frequency firing in interneurons, raising the possibility that MEAK is associated with reduced interneuronal function. To determine how this variant triggers MEAK, we expressed KV3.1bR320H in cortical interneurons in vitro and investigated the effects on neuronal function and morphology. We also performed electrophysiological recordings of oocytes expressing KV3.1b to determine whether the mutation introduces gating pore currents. Expression of the KV3.1bR320H variant profoundly reduced excitability of mature cortical interneurons, and cells expressing these channels were unable to support high‐frequency firing. The mutant channel also had an unexpected effect on morphology, severely impairing neurite development and interneuron viability, an effect that could not be rescued by blocking KV3 channels. Oocyte recordings confirmed that in the adult KV3.1b isoform, R320H confers a dominant negative loss‐of‐function effect by slowing channel activation, but does not introduce potentially toxic gating pore currents. Overall, our data suggest that, in addition to the regulation of high‐frequency firing, KV3.1 channels play a hitherto unrecognized role in neuronal development. MEAK may be described as a developmental dendritopathy.
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影响因子：
5.3
作者：
Lovell, PV;McCobb, DP
通讯作者：
McCobb, DP
影响因子：
4.8
作者：
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作者：
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通讯作者：
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