The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin.
The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin.
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作者：
Barker BS;Ottolini M;Wagnon JL;Hollander RM;Meisler MH;Patel MK
SCN 8A脑病（EIEE 13）是由功能获得性突变引起的，导致电压门控钠通道Nav1.6过度活跃。该通道集中在轴突起始段（AIS），并参与建立神经元兴奋性。SCN 8A脑病的临床特征包括0-18个月龄之间的癫痫发作、智力残疾和发育迟缓。癫痫发作通常难以用标准抗癫痫药物治疗，并且在大约10%的患者中报告了癫痫猝死（SUDEP）。在最近的一项研究中，高剂量的苯妥英对4名SCN 8A脑病患者有效。鉴于这一观察结果，我们研究了SCN 8A突变p.Ile1327Val的功能效应与其对苯妥英的反应之间的关系。通过定点突变将突变引入Scn 8a cDNA中。在转染的ND 7/23细胞中表征通道活性。比较了苯妥英钠（100 μM）对突变型和野生型（WT）通道的影响。通道激活参数在突变体通道中以超极化方向移动，而失活参数以去极化方向移动，增加Na通道窗口电流。I1327 V通道的宏观电流衰减减慢，表明从开放状态到失活状态的转变受损。通道停用也被延迟，允许更多的通道保持开放状态。苯妥英（100 μM）导致超极化激活和失活曲线以及I1327 V突变体通道的紧张性阻滞和使用依赖性阻滞大于WT。SCN 8A-I1327 V是一种功能获得性突变，具有改变的特征，预计可增加神经元兴奋性和癫痫发作易感性。苯妥英是突变通道的有效抑制剂，可用于治疗SCN 8A功能获得性突变患者。
SCN8A encephalopathy (EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0–18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard anti-epileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin. The mutation was introduced into the Scn8a cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μM) on mutant and wild type (WT) channels were compared. Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, while inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μM) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use dependent block of I1327V mutant channels relative to WT. SCN8A – I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain-of-function mutations of SCN8A.
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DOI：
10.1007/s13311-015-0372-8
发表时间：
2016-01
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Boerma RS;Braun KP;van den Broek MP;van Berkestijn FM;Swinkels ME;Hagebeuk EO;Lindhout D;van Kempen M;Boon M;Nicolai J;de Kovel CG;Brilstra EH;Koeleman BP
通讯作者：
Koeleman BP
影响因子：
3.4
作者：
Wagnon JL;Meisler MH
通讯作者：
Meisler MH
影响因子：
3.3
作者：
Ellerkmann, RK;Remy, S;Beck, H
通讯作者：
Beck, H
影响因子：
1.9
作者：
Vaher, Ulvi;Noukas, Margit;Talvik, Tiina
通讯作者：
Talvik, Tiina
影响因子：
4
作者：
Blanchard MG;Willemsen MH;Walker JB;Dib-Hajj SD;Waxman SG;Jongmans MC;Kleefstra T;van de Warrenburg BP;Praamstra P;Nicolai J;Yntema HG;Bindels RJ;Meisler MH;Kamsteeg EJ
通讯作者：
Kamsteeg EJ