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

Takayama, Koichiro; Ohno, Seiko; Ding, Wei‐Guang; Ashihara, Takashi; Fukumoto, Daisuke; Wada, Yuko; Makiyama, Takeru; Kise, Hiroaki; Hoshiai, Minako; Matsuura, Hiroshi; Horie, Minoru

doi:10.1016/j.hrthm.2019.05.033

Cited by 33 publications

(46 citation statements)

References 30 publications

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“…9 Genetic variants in KCND3 are also associated with cardiac arrhythmia and sudden unexpected death (SUD). 4,11,12 Functional analyses of some of the KCND3 mutations demonstrated either channel dysfunction or reduced cell membrane trafficking. [2][3][4][5]10,13 These abnormalities are often attenuated by co-expression of potassium channel interacting protein 2 (KChIP2).…”

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confidence: 99%

V374A KCND3 Pathogenic Variant Associated With Paroxysmal Ataxia Exacerbations

Paucar

Ågren

et al. 2021

Neurol Genet

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ObjectiveAtaxia channelopathies share common features such as slow motor progression and variable degrees of cognitive dysfunction. Mutations in potassium voltage-gated channel subfamily D member 3 (KCND3), encoding the K+ channel, Kv4.3, are associated with spinocerebellar ataxia (SCA) 19, allelic with SCA22. Mutations in potassium voltage-gated channel subfamily C member 3 (KCNC3), encoding another K+ channel, Kv3.3, cause SCA13. First, a comprehensive phenotype assessment was carried out in a family with autosomal dominant ataxia harboring 2 genetic variants in KCNC3 and KCND3. To evaluate the physiological impact of these variants on channel currents, in vitro studies were performed.MethodsClinical and psychometric evaluations, neuroimaging, and genotyping of a family (mother and son) affected by ataxia were carried out. Heterozygous and homozygous Kv3.3 A671V and Kv4.3 V374A variants were evaluated in Xenopus laevis oocytes using 2-electrode voltage-clamp. The influence of Kv4 conductance on neuronal activity was investigated computationally using a Purkinje neuron model.ResultsThe main clinical findings were consistent with adult-onset ataxia with cognitive dysfunction and acetazolamide-responsive paroxysmal motor exacerbations in the index case. Despite cognitive deficits, fluorodeoxyglucose (FDG)-PET displayed hypometabolism mainly in the severely atrophic cerebellum. Genetic analyses revealed the new variant c.1121T>C (V374A) in KCND3 and c.2012T>C (A671V) in KCNC3. In vitro electrophysiology experiments on Xenopus oocytes demonstrated that the V374A mutant was nonfunctional when expressed on its own. Upon equal co-expression of wild-type (WT) and V374A channel subunits, Kv4.3 currents were significantly reduced in a dominant negative manner, without alterations of the gating properties of the channel. By contrast, Kv3.3 A671V, when expressed alone, exhibited moderately reduced currents compared with WT, with no effects on channel activation or inactivation. Immunohistochemistry demonstrated adequate cell membrane translocation of the Kv4.3 V374A variant, thus suggesting an impairment of channel function, rather than of expression. Computational modeling predicted an increased Purkinje neuron firing frequency upon reduced Kv4.3 conductance.ConclusionsOur findings suggest that Kv4.3 V374A is likely pathogenic and associated with paroxysmal ataxia exacerbations, a new trait for SCA19/22. The present FDG PET findings contrast with a previous study demonstrating widespread brain hypometabolism in SCA19/22.

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confidence: 99%

V374A KCND3 Pathogenic Variant Associated With Paroxysmal Ataxia Exacerbations

Paucar

Ågren

et al. 2021

Neurol Genet

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“…Moreover, a missense variant in the C-terminus, p.R431C, was linked to episodic ataxia [38] and a de novo duplication of KCND3 was reported to cause early repolarization syndrome [39]. Furthermore, Takayama et al recently reported the K v 4.3 GOF variant, p.G306A, to be responsible for early repolarization syndrome, refractory epilepsy, intellectual disability and paroxysmal atrial fibrillation [40]. Collectively, these studies provide further support for the hypothesis that GOF variants in KCND3 may share a common pathway to cardiac and neuronal channelopathies sometimes in the same patient.…”

Section: Discussionmentioning

confidence: 99%

Inter-Regulation of Kv4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies

Clatot

Neyroud

Cox

et al. 2020

IJMS

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Background: Genetic variants in voltage-gated sodium channels (Nav) encoded by SCNXA genes, responsible for INa, and Kv4.3 channels encoded by KCND3, responsible for the transient outward current (Ito), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that Kv4.3 and Nav variants regulate each other’s function, thus modulating INa/Ito balance in cardiomyocytes and INa/I(A) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Nav1.5 and Kv4.3 channels in HEK293 cells. INa and Ito were recorded. Results: SCN5A variants associated with BrS reduced INa, but increased Ito. Moreover, BrS and SCA19/22 KCND3 variants associated with a gain of function of Ito, significantly reduced INa, whereas the SCA19/22 KCND3 variants associated with a loss of function (LOF) of Ito significantly increased INa. Auxiliary subunits Navβ1, MiRP3 and KChIP2 also modulated INa/Ito balance. Co-immunoprecipitation and Duolink studies suggested that the two channels interact within the intracellular compartments and biotinylation showed that LOF SCN5A variants can increase Kv4.3 cell-surface expression. Conclusion: Nav and Kv4.3 channels modulate each other’s function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.

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“…Data suggest that ER syndrome may be associated with proarrhythmic inherited mutations. Mutations that have been reported responsible are shown in Table . Gain‐of‐function mutations in the potassium channel genes result in increased outward potassium current and is associated with ER and idiopathic VF.…”

Section: Genes Linked To Early Repolarizationmentioning

confidence: 99%

“…Mutations that have been reported responsible are shown in Table 1. [7][8][9][10][11][12][13][14][15] Gain-of-function mutations in the potassium channel genes result in increased outward potassium current and is associated with ER and idiopathic VF. Loss-of-function mutations in genes for cardiac L-type calcium channels and sodium channels have been linked to ER syndrome as well.…”

Section: Mortality Risk Of Early Repolarization Patternmentioning

confidence: 99%