β1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function
β1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function
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DOI：
10.1523/jneurosci.0405-16.2016
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发表时间：
2016-06-08
影响因子：
5.3
通讯作者：
Isom, Lori L.
中科院分区：
文献类型：
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作者：
Kruger, Larisa C.;O'Malley, Heather A.;Isom, Lori L.
电压门控钠通道(VGSC) β亚基在多个时间尺度上通过多种途径发出信号。除了调节钠和钾电流外，β亚基还作为细胞粘附分子发挥非导电作用，这使它们能够在细胞间通讯、神经元迁移、神经突生长、神经元寻路和轴突束化中发挥作用。编码VGSC β 1和β 1B的SCN1B突变与癫痫有关。常染色体显性SCN1B-C121W是第一个确定的与癫痫相关的VGSC突变，可导致遗传性癫痫伴发热性癫痫发作（GEFS+）。这种突变已被证明破坏了在异源系统中表达的β 1亚基的钠电流调节和细胞粘附功能。本研究的目的是比较Scn1b-C121W杂合基因（Scn1b(+/W)）与Scn1b-空等位基因（Scn1b(+/-)）的小鼠杂合基因，以确定C121W突变是否会导致体内功能丧失。我们发现Scn1b（+/W）小鼠比Scn1b（-/-）和Scn1b（-/-）小鼠更容易发生高热引起的惊厥，这是一种小儿热性惊厥模型。β 1-C121W亚基在体内神经元细胞表面表达。然而，尽管如此，β 1-C121W多肽不完全糖基化，并且不与大脑中的VGSC α亚基相关。β 1-C121W亚细胞定位局限于神经元细胞体，在Scn1b（W/W）小鼠的皮层或小脑的轴突初始段或视神经结中未检测到。这些数据，加上我们之前的结果显示β 1-C121W不能参与反亲同细胞粘附，导致假设SCN1B-C121W在人类GEFS+患者中赋予了有害的功能获得。
Voltage-gated sodium channel (VGSC) beta subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, beta subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell-cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC beta 1 and beta 1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of beta 1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b(+/W)) with mice heterozygous for the Scn1b-null allele (Scn1b(+/-)) to determine whether the C121W mutation results in loss-of-function in vivo. We found that Scn1b(+/W) mice were more susceptible than Scn1b(-/-) and Scn1b(-/-) mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. beta 1-C121W subunits are expressed at the neuronal cell surface in vivo. However, despite this, beta 1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC alpha subunits in the brain. beta 1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1b(W/W) mice. These data, together with our previous results showing that beta 1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients.