Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, UK.
Sci Rep. 2016 Sep 1;6:31879. doi: 10.1038/srep31879.
Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures. The patient carries a heterozygous missense variant (c3818C > T; pAla1273Val) in the NaV1.1 brain sodium channel. We compared the functional effects of the variant vs. wild type NaV1.1 using patch clamp recordings from channels expressed in Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40 °C). The variant channels produced a temperature-dependent destabilization of activation and fast inactivation. Implementing these empirical abnormalities in a computational model predicts a higher threshold for depolarization block in the variant, particularly at 40 °C, suggesting a failure to autoregulate at high-input states. These results reveal direct effects of abnormalities in NaV1.1 biophysical properties on neuronal dynamics. They illustrate the value of combining cellular measurements with computational models to integrate different observational scales (gene/channel to patient).
德拉维雷综合征是 SCN1A 基因突变相关癫痫的典型代表。其特征是长时间发作，通常由发热引发。我们描述了对一名具有早期发热敏感性发作的儿童中 SCN1A 突变的评估。该患者携带脑钠通道的 NaV1.1 中的杂合错义变异（c3818C>T;pAla1273Val）。我们使用在中国仓鼠卵巢细胞中表达的通道，在不同温度（32、37 和 40°C）下进行膜片钳记录，比较了变异与野生型 NaV1.1 的功能效应。变异通道产生了温度依赖性的激活和快速失活不稳定。在计算模型中实施这些经验异常预测在变异体中去极化阻断的阈值更高，特别是在 40°C 时，表明在高输入状态下无法自我调节。这些结果揭示了 NaV1.1 生物物理特性异常对神经元动力学的直接影响。它们说明了将细胞测量与计算模型相结合以整合不同观测尺度（基因/通道到患者）的价值。
