Functional and pharmacological investigation of novel and de novo KCND3 variants identified in patients with neurodevelopmental disorders

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Abstract
Sudden unexpected death in epilepsy (SUDEP) is one of the most frequent causes of death in patients with epilepsy, though the pathogenesis of SUDEP has not been well elucidated. Here, we report novel heterozygous KCND3 variants, p.V401L and p.V401M, identified in young patients with refractory epilepsy (RE) and neurodevelopmental disorders, and the functional properties of these variants. We aimed to investigate the electrophysiological changes in de novo KCND3 variants and analyse the pharmacological effects of quinidine on these variants. Chinese hamster ovary (CHO) cells were transiently co-transfected with wild-type (WT) and/or variant KCND3 and Kcnip2. Transient outward potassium currents (Ito) were recorded using the whole-cell patch-clamp method. The inhibitory effect of quinidine on Ito was evaluated. In electrophysiological analysis, CHO cells expressing the variant channels showed a significant increase in current density compared with those expressing WT channels. The Ito activation curves were shifted significantly to the left, and significantly slower inactivation time constants were observed in both variant channels. Recovery from inactivation of the variant channels was significantly slower than that of WT. Quinidine suppressed Ito in a concentration-dependent manner and accelerated the slow inactivation of variant channels. In conclusion, de novo KCND3 variants identified in patients with RE and neurodevelopmental disorders showed gain and loss of function effects on Ito. These patients may be at risk of developing early repolarization syndrome, leading to SUDEP. Increased Ito was suppressed by quinidine, suggesting that it may be an effective therapy for RE and possibly for preventing SUDEP.
Funding Information
  • SENSHIN Medical Research Foundation
  • MEXT | Japan Society for the Promotion of Science (22K20906)
  • MEXT | Japan Society for the Promotion of Science (24K19074)
  • MEXT | Japan Society for the Promotion of Science (19K17593)

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