2023 Fiscal Year Final Research Report
Functional and pharmacological investigation on novel KCND3 variants identified in patients with early repolarization syndrome and refractory epilepsy
| Project/Area Number |
22K20906
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
Byambajav Tserenlkham 国立研究開発法人国立循環器病研究センター, オープンイノベーションセンター, リサーチフェロー (60963527)
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| Project Period (FY) |
2022-08-31 – 2024-03-31
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| Keywords | KCND3 / potassium channel / gain of function change / quinidine / SSRIs |
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| Outline of Final Research Achievements |
De novo and heterozygous KCND3 variants, p.V401L and p.V401M were identified in two young patients with refractory epilepsy. In the electrophysiological analysis, Chinese Hamster Ovary (CHO) cells expressing variant channels showed significant increase of current densities compared to those with WT. The activation curves of Ito with variants significantly shifted to leftward. In addition, significant slow inactivation time constants were observed. Related to the slow inactivation of variants, the recovery from inactivation in variants channels was significantly slow. We next conducted pharmacological investigation and examined the inhibitory effect of quinidine and Selective Serotonin Reuptake Inhibitors (SSRIs). Micromolar concentration of quinidine and SSRIs normalized the slow inactivation of variant channels in a concentration-dependent manner.
The variant carrying patients might have risk of sudden cardiac death in epilepsy, and quinidine and SSRIs can be therapeutic options.
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| Free Research Field |
Cardiology
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| Academic Significance and Societal Importance of the Research Achievements |
De novo and heterozygous KCND3 variants, p.V401L and p.V401M were identified and the gain-of-functional changes of these Ito channels by a KCND3 variants were reversed by quinidine and SSRIs. Therefore, these candidates can be therapeutic options to prevent sudden cardiac death in epilepsy.
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