The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes

Calloe, Kirstine; Geryk, Michelle; Freude, Kristine; Treat, Jacqueline A.; Vold, Victoria A; Frederiksen, Henriette R.; Broendberg, Anders Krogh; Frederiksen, Tanja Charlotte; Jensen, Henrik Kjærulf; Cordeiro, Jonathan M.

doi:10.1093/europace/euac090

Cited by 9 publications

(13 citation statements)

References 20 publications

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“…15,34 One variant, G213D which substitutes a bulky aspartate for a small glycine in the Na V 1.5 domain 1 S3-S4 linker, has been reported to generate both a large window current and a gating pore current at negative potentials. 13 G213D iPSC-CMs displayed afterdepolarizations that were corrected with flecainide; whether G213D interacts with the GCTC was not addressed.…”

Section: Discussionmentioning

confidence: 99%

“…These mutations are thought to generate a second (non-physiologic) ion permeation pathway in the S1-S4 gating region, leading to a “gating pore” current or omega current. 6,9,10 Several additional variants that are not in S4 arginines have been described in MEPPC (A204E, 11 L828F, 12 G213D, 13 and M1851V 14 ) and these variants are mainly thought to act through alternate mechanisms such as shifts in the voltage-dependence of channel activation and/or inactivation generating an increased “window current”.…”

Section: Introductionmentioning

confidence: 99%

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Multifocal Ectopic Purkinje Premature Contractions due to neutralization of anSCN5Anegative charge: structural insights into the gating pore hypothesis

Glazer,

Yang,

et al. 2024

Preprint

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Background: We identified a novel SCN5A variant, E171Q, in a neonate with very frequent ectopy and reduced ejection fraction which normalized after arrhythmia suppression by flecainide. This clinical picture is consistent with multifocal ectopic Purkinje-related premature contractions (MEPPC). Most previous reports of MEPPC have implicated SCN5A variants such as R222Q that neutralize positive charges in the S4 voltage sensor helix of the channel protein NaV1.5 and generate a gating pore current. Methods and Results: E171 is a highly conserved negatively-charged residue located in the S2 transmembrane helix of NaV1.5 domain I. E171 is a key component of the Gating Charge Transfer Center, a region thought to be critical for normal movement of the S4 voltage sensor helix. We used heterologous expression, CRISPR-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and molecular dynamics simulations to demonstrate that E171Q generates a gating pore current, which was suppressed by a low concentration of flecainide (IC50 = 0.71±0.07 uM). R222Q shifts voltage dependence of activation and inactivation in a negative direction but we observed positive shifts with E171Q. E171Q iPSC-CMs demonstrated abnormal spontaneous activity and prolonged action potentials. Molecular dynamics simulations revealed that both R222Q and E171Q proteins generate a water-filled permeation pathway that underlies generation of the gating pore current. Conclusion: Previously identified MEPPC-associated variants that create gating pore currents are located in positively-charged residues in the S4 voltage sensor and generate negative shifts in the voltage dependence of activation and inactivation. We demonstrate that neutralizing a negatively charged S2 helix residue in the Gating Charge Transfer Center generates positive shifts but also create a gating pore pathway. These findings implicate the gating pore pathway as the primary functional and structural determinant of MEPPC and widen the spectrum of variants that are associated with gating pore-related disease in voltage-gated ion channels.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multifocal Ectopic Purkinje Premature Contractions due to neutralization of anSCN5Anegative charge: structural insights into the gating pore hypothesis

Glazer,

Yang,

et al. 2024

Preprint

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“… 126 The G213D variant in Nav1.5 in the SCN5A gene is associated with a severe form of arrhythmic DCM that may be cure by antiarrhythmic drugs. 127 The role of common variants has also been reported thanks to GWAS analysis that have identified new DCM-associated SNPs. 128 Polygenic risk scores have recently been shown to have predictive value for DCM prognostic.…”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies

Crotti,

Brugada,

Calkins

et al. 2023

Europace

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In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1–3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype–phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

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“…In a recent study, Calloe et al demonstrated that flecainide treatment reduced the window current in hiPSC-CMs with the SCN5A -G231D mutation, and had beneficial effects in patients carrying this mutation. 117 Despite the well-established link with Na + channels, SCN5A mutations are found in only 20% of BrS patients, and their presence is not necessarily always causally related since SCN5A genetic variants are frequently observed in the general population, some of which do not affect Na + channel function. 118 Overall, BrS is characterized by extensive variability in disease severity as well as reduced penetrance, and a polygenic basis is now increasingly recognized.…”

Section: Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyop...mentioning

confidence: 99%

25 years of basic and translational science in EP Europace: novel insights into arrhythmia mechanisms and therapeutic strategies

Remme,

Heijman,

Gomez

et al. 2023

Europace

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In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial fibrillation to ventricular tachyarrhythmias), different diseases predisposing to arrhythmia formation (such as genetic arrhythmia disorders and heart failure), and different interventional and pharmacological anti-arrhythmic treatment strategies (ranging from pacing and defibrillation to different ablation approaches and novel drug-therapies). These studies have been conducted in cellular models, small and large animal models, and in the last couple of years increasingly in silico using computational approaches. In sum, these articles have contributed substantially to our pathophysiological understanding of arrhythmia mechanisms and treatment options; many of which have made their way into clinical applications. This review discusses a representative selection of EP Europace manuscripts covering the topics of pacing and ablation, atrial fibrillation, heart failure and pro-arrhythmic ventricular remodelling, ion channel (dys)function and pharmacology, inherited arrhythmia syndromes, and arrhythmogenic cardiomyopathies, highlighting some of the advances of the past 25 years. Given the increasingly recognized complexity and multidisciplinary nature of arrhythmogenesis and continued technological developments, basic and translational electrophysiological research is key advancing the field. EP Europace aims to further increase its contribution to the discovery of arrhythmia mechanisms and the implementation of mechanism-based precision therapy approaches in arrhythmia management.

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The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes

Cited by 9 publications

References 20 publications

Multifocal Ectopic Purkinje Premature Contractions due to neutralization of anSCN5Anegative charge: structural insights into the gating pore hypothesis

Multifocal Ectopic Purkinje Premature Contractions due to neutralization of anSCN5Anegative charge: structural insights into the gating pore hypothesis

From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies

25 years of basic and translational science in EP Europace: novel insights into arrhythmia mechanisms and therapeutic strategies

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