Novel Cardiocerebral Channelopathy Associated with a &lt;i&gt;KCND3&lt;/i&gt; V392I Mutation

Nakajima, Tadashi; Kawabata‐Iwakawa, Reika; Kaneko, Yoshiaki; Hamano, Shin‐ichiro; Sano, Rie; Tamura, Shuntaro; Hasegawa, Hiroshi; Kobari, Takashi; Kominato, Yoshihiko; Nishiyama, Masahiko; Kurabayashi, Masahiko

doi:10.1536/ihj.20-203

Cited by 8 publications

(21 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure 2, these two mutations increase Kv4.3/I to during bradycardia, thereby leading to J wave augmentation and shortening of the QTc interval, while it decreases the increased Kv4.3/I to during tachycardia, thereby leading to the decrease/disappearance of the J wave and normalization of the QTc interval in both the ventricle and atrium. An increase of J wave amplitude during bradycardia may be consistent with the fact that one patient with this mutation suddenly died at midnight [13]. Regarding PAF, a shortening of the APD in the atrium during bradycardia may contribute to the occurrence of AF, possibly consistent with the fact that PAF predominantly occurs at night or in the early morning [13].…”

Section: Erssupporting

confidence: 59%

“…Among causal genes for ERS, KCND3 mutations were recently identified [13,138]. KCND3 encodes Kv4.3 composing transient outward potassium currents (I to or I A ), and it is expressed in both the heart and brain [140].…”

Section: Ersmentioning

confidence: 99%

“…We recently identified a KCND3 V392I mutation in a familial case (mid to late teen sisters) with both cardiac (ERS, PAF) and cerebral (epilepsy, which manifested in early childhood, and ID) phenotypes [13]. Giudicessi et al reported that the KCND3 V392I mutation displayed a unique mixed electrophysiological property: An increase of Kv4.3 (due to an increased current density and delayed inactivation) and a decrease of the increased Kv4.3 (due to a delayed recovery from inactivation) [146], which resemble those of the KCND3 G306A mutation [138].…”

Section: Ersmentioning

confidence: 99%

“…These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Nakajima

Tamura

Kurabayashi

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

show abstract

Section: Erssupporting

confidence: 59%

Section: Ersmentioning

confidence: 99%

Section: Ersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Nakajima

Tamura

Kurabayashi

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, gain-of-function mutations in the KCND3 gene are linked to cardiac arrhythmia, the Brugada syndrome [ 11 ]. Nonetheless, some of the cardiopathogenic gain-of-function KCND3 mutations may also be related to neurological disorders such as ataxia, cognitive dysfunction, and epilepsy [ 10 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Rare Gain-of-Function KCND3 Variant Associated with Cerebellar Ataxia, Parkinsonism, Cognitive Dysfunction, and Brain Iron Accumulation

Hsiao

Tropea

et al. 2021

IJMS

View full text Add to dashboard Cite

Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.

show abstract

Gene mutations in comorbidity of epilepsy and arrhythmia

Deng

2022

J Neurol

View full text Add to dashboard Cite

Novel Cardiocerebral Channelopathy Associated with a <i>KCND3</i> V392I Mutation

Cited by 8 publications

References 19 publications

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Rare Gain-of-Function KCND3 Variant Associated with Cerebellar Ataxia, Parkinsonism, Cognitive Dysfunction, and Brain Iron Accumulation

Gene mutations in comorbidity of epilepsy and arrhythmia

Contact Info

Product

Resources

About