A de novo gain-of-function KCND3 mutation in early repolarization syndrome

Abstract Background Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential, therefore, the transient outward potassium current (I to ) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an α-subunit of the I to channel, is considered as one of target genes. Objective We aimed to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis. Methods We performed genetic screening for 11 unrelated probands with ERS and analyzed electrophysiological property of detected mutations by patch-clamp methods. Results A novel, de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in one proband. The proband was 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing the VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild-type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms. Conclusion A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explainable by the increased I to . Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting the effective treatment.