Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy
Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy
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DOI：
10.1111/j.1528-1167.2006.00643.x
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发表时间：
2006-10-01
期刊：
影响因子：
5.6
通讯作者：
George, Alfred L., Jr.
中科院分区：
文献类型：
--
作者：
Ohmori, Iori;Kahlig, Kristopher M.;George, Alfred L., Jr.
目的：SCN 1A编码人Na（V）1.1神经元电压门控钠通道，其突变导致婴儿严重肌阵挛性癫痫综合征（SMEI）。预计大多数SMEI相关突变会截短SCN 1A蛋白，可能导致钠通道功能丧失。然而，在这种疾病中也报道了许多错义或框内缺失SCN 1A突变，但其功能影响在很大程度上是未知的。在这里，我们报告了8个SCN 1A突变的功能特征，（G177 E、I227 S、R393 H、Y426 N、H939 Q、C959 R、delF1289和T1909 I）。在重组人SCN 1A中构建SCN 1A突变体，然后在人tsA 201细胞中沿着人β（1）和β（2）钠通道辅助亚基。全细胞膜片钳记录被用来定义每个突变体的生物物理特性，并与野生型（WT）channel.Results比较：6个突变体是非功能性的，但Y 426 N和T1909 I产生可测量的钠通道活性。表达Y 426 N和T1909 I的细胞与WT-SCN 1A相比具有显著更低的电流密度。此外，其他生物物理异常观察到的两个功能突变体，包括降低通道的可用性（Y 426 N）和增加持续钠电流（T1909 I）。结论：我们得出结论，SMEI是由SCN 1A功能的完全丧失，或功能失调的钠通道表现出混合的生物物理特性。在SCN 1A突变中观察到的这种广泛的功能缺陷表明，SMEI可能由不止一种分子或细胞机制引起，或者需要其他致病因素。
Purpose: Mutations in SCN1A, encoding the human Na(V)1.1 neuronal voltage-gated sodium channel, cause the syndrome of severe myoclonic epilepsy of infancy (SMEI). Most SMEI-associated mutations are predicted to truncate the SCN1A protein, likely causing a loss of sodium channel function. However, many missense or in-frame deletion SCN1A mutations have also been reported in this disorder, but their functional impact is largely unknown. Here we report the functional characterization of eight SCN1A mutations (G177E, I227S, R393H, Y426N, H939Q, C959R, delF1289, and T1909I) previously identified in SMEI probands.Methods: SCN1A mutants were constructed in a recombinant human SCN1A and then heterologously expressed in human tsA201 cells along with the human beta(1) and beta(2) sodium channel accessory subunits. Whole-cell patch-clamp recording was used to define biophysical properties of each mutant and for comparison with the wild-type (WT) channel.Results: Six of the mutants were nonfunctional, but Y426N and T1909I generated measurable sodium channel activity. Cells expressing Y426N and T1909I had significantly lower current densities compared with WT-SCN1A. In addition, other biophysical abnormalities were observed for the two functional mutants including decreased channel availability (Y426N) and increased persistent sodium current (T1909I).Conclusions: We conclude that SMEI is caused either by complete loss of SCN1A function, or by dysfunctional sodium channels exhibiting mixed biophysical properties. This wide spectrum of functional defects observed among SCN1A mutations suggests that SMEI may result from more than a single molecular or cellular mechanism, or require other factors for pathogenesis.