SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs

Qian-bei Guo1,2, Li Zhan1, Hai-yan Xu1, Zhao-bing Gao1,2,3, Yue-ming Zheng1
1 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
Correspondence to: Zhao-bing Gao:, Yue-ming Zheng:,
DOI: 10.1038/s41401-022-00955-x
Received: 26 February 2022
Accepted: 5 July 2022
Advance online: 27 July 2022


De novo missense mutations in SCN8A gene encoding voltage-gated sodium channel NaV1.6 are linked to a severe form of early infantile epileptic encephalopathy named early infantile epileptic encephalopathy type13 (EIEE13). The majority of the patients with EIEE13 does not respond favorably to the antiepileptic drugs (AEDs) in clinic and has a significantly increased risk of death. Although more than 60 EIEE13-associated mutations have been discovered, only few mutations have been functionally analyzed. In this study we investigated the functional influences of mutations N1466T and N1466K, two EIEE13-associated mutations located in the inactivation gate, on sodium channel properties. Sodium currents were recorded from CHO cells expressing the mutant and wide-type (WT) channels using the whole-cell patch-clamp technique. We found that, in comparison with WT channels, both the mutant channels exhibited increased window currents, persistent currents (INaP) and ramp currents, suggesting that N1466T and N1466K were gain-of-function (GoF) mutations. Sodium channel inhibition is one common mechanism of currently available AEDs, in which topiramate (TPM) was effective in controlling seizures of patients carrying either of the two mutations. We found that TPM (100 μM) preferentially inhibited INaP and ramp currents but did not affect transient currents (INaT) mediated by N1466T or N1466K. Among the other 6 sodium channel-inhibiting AEDs tested, phenytoin and carbamazepine displayed greater efficacy than TPM in suppressing both INaP and ramp currents. Functional characterization of mutants N1466T and N1466K is beneficial for understanding the pathogenesis of EIEE13. The divergent effects of sodium channel-inhibiting AEDs on INaP and ramp currents provide insight into the development of therapeutic strategies for the N1466T and N1466K-associated EIEE13.
Keywords: early infantile epileptic encephalopathy type 13; SCN8A; gain-of-function mutation; antiepileptic drugs; phenytoin; carbamazepine

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