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

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Abstract

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 SCN9A mutations 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 SCN9A mutants contribute to an increase in seizure, and show distinct sensitivity to OXC.

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Acknowledgements

We are grateful to Prof. Ren Lai and Shilong Yang (Kunming Institute of Zoology, Chinese Academy of Sciences) for providing the pEZ-Lv206-hNav1.7 plasmid. This work was supported by the National Natural Science Foundation of China (81603410, 31571032, and 31771191), the Shanghai Municipal Commission of Health and Family Planning Foundation (20184Y0086), Innovation Program of Shanghai Municipal Education Commission (15ZZ063), the Research Project of Putuo Hospital, Shanghai University of Traditional Chinese Medicine (2016102A and 2016208A), and a Project for Capacity Promotion of Putuo District Clinical Special Disease.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Shuzhang Zhang, Zhiping Zhang, Jingkang Guo & Yonghua Ji

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

    Yuan Shen, Yudan Zhu & Jie Tao

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

    Kun Du

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

    Yonghua Ji

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

    Jie Tao

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  1. Shuzhang Zhang
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Correspondence to Yonghua Ji or Jie Tao.

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Zhang, S., Zhang, Z., Shen, Y. et al. SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine. Neurosci. Bull. 36, 11–24 (2020). https://doi.org/10.1007/s12264-019-00413-5

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  • DOI: https://doi.org/10.1007/s12264-019-00413-5

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