SCN9A Epileptic Encephalopathy Mutations Display a Gain-offunction Phenotype and Distinct Sensitivity to Oxcarbazepine

Shuzhang Zhang1 • Zhiping Zhang1 • Yuan Shen2 • Yudan Zhu2 • Kun Du3 • Jingkang Guo1 • Yonghua Ji 1,4 • Jie Tao 2,5

1 Institute of Biomembrane and Biopharmaceutics, Shanghai University, Shanghai 200444, China

2 Central Laboratory and Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China

3 Department of Clinical Laboratory, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 202150, China

4 Xinhua Translational Institute for Cancer Pain, Xinhua Hospital Chongming Branch, Shanghai 202150, China

5 Putuo Clinical Medical School, Anhui Medical University, Shanghai 200062, China


Genetic mutants of voltage-gated sodium channels (VGSCs) are considered to be responsible for the increasing number of epilepsy syndromes. Previous research has indicated that mutations of one of the VGSC genes, SCN9A (Nav1.7), result in febrile seizures and Dravet syndrome in humans. Despite these recent efforts, the electrophysiological basis of SCN9Amutations remains unclear. Here, we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A (W1150R). Electrophysiological characterization of different SCN9A mutants in HEK293T cells, the previously-reported N641Y and K655R variants, as well as the newly-found W1150R variant, revealed that the current density of the W1150R and N641Y variants was significantly larger than that of the wild-type (WT) channel. The time constants of recovery from fast inactivation of the N641Y and K655R variants were markedly lower than in the WT channel. The W1150R variant caused a negative shift of the G–V curve in the voltage dependence of steady-state activation. All mutants displayed persistent currents larger than the WT channel. In addition, we found that oxcarbazepine (OXC), one of the antiepileptic drugs targeting VGSCs, caused a significant shift to more negative potential for the activation and inactivation in WT and mutant channels. OXC-induced inhibition of currents was weaker in the W1150R variant than in the WT. Furthermore, with administering OXC the time constant of the N641Y variant was longer than those of the other two SCN9A mutants. In all, our results indicated that the point mutation W1150R resulted in a novel gain-of-function variant. These findings indicated that SCN9Amutants contribute to an increase in seizure, and show distinct sensitivity to OXC.


Voltage-gated sodium channel; SCN9A; Epilepsy; Electrophysiological function; Oxcarbazepine; Sensitivity


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