Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation

Lieve, Krystien V.V.; Verkerk, Arie O.; Podliesna, Svitlana; Werf, Christian van der; Tanck, Michael W.T.; Hofman, Nynke; Bergen, Paul Fmm van; Beekman, Leander; Bezzina, Connie R.; Wilde, Arthur A.M.; Lodder, Elisabeth M.

doi:10.1016/j.ijcard.2017.01.113

Cited by 33 publications

(33 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, although the positive shift of activation curve and increase in current density in R800H were not statistically significant, both resembled the functional changes of gain‐of‐function mutations, which are found in the patients with atrial fibrillation or those with PVCs 15,16 . In addition to the fast recovery from inactivation state, these small functional changes in R800H Na + channel might predispose to scTdP.…”

Section: Discussionmentioning

confidence: 79%

SCN5A mutation identified in a patient with short‐coupled variant of torsades de pointes

Sonoda

Ohno

Shimizu

et al. 2020

Pacing Clinical Electrophis

View full text Add to dashboard Cite

Background: Short-coupled variant of torsades de pointes (scTdP) is a disease characterized by TdP without QT prolongation, which is initiated by extremely short-coupled ventricular extrasystoles. Its genetic background remains rarely unveiled. Objective:We aimed to identify genetic variations in patients with scTdP and to analyze the functional change of the mutant Na + channel identified in a scTdP patient. Methods and results:We performed genetic analysis for inherited arrhythmia-related 45 genes using next-generation sequencer (MiSeq, Illumina) among seven consecutive scTdP patients. We identified an SCN5A mutation R800H in a 38-year-old male who suffered ventricular fibrillation during dinner and was resuscitated. Two months later, he lost his consciousness at work. His Holter electrocardiogram showed scTdP. He had no family history of sudden cardiac death or heart disease. Functional analysis of the SCN5A-R800H channels showed a significantly shortened recovery time from inactivation. Peak sodium current densities in SCN5A-R800H were larger than those in wild type but the difference was not statistically significant. Conclusions:We identified an SCN5A mutation in a scTdP patient and confirmed that the mutant channel caused the shortness of recovery time from inactivation. SCN5A might be a candidate gene for scTdP.

show abstract

Section: Discussionmentioning

confidence: 79%

SCN5A mutation identified in a patient with short‐coupled variant of torsades de pointes

Sonoda

Ohno

Shimizu

et al. 2020

Pacing Clinical Electrophis

View full text Add to dashboard Cite

show abstract

“…Not surprisingly, some genes associated with AF in LQTS have overlap with familial AF: LQT1 (KCNQ1), LQT2 (KCNH2), LQT3 (SCN5a), and LQT7 (KCNJ2). However, for potassium channels, in LQTS the genetic defect results in ‘loss of function’ in contrast to a ‘gain of function’ in familial AF 245,246 . It is less clear how prolonged repolarization results in AF susceptibility but it may involve similar mechanisms to torsade de pointes 247 or perhaps dispersion of repolarization and induction of early after depolarizations 248,249 …”

Section: How To Assess Risk For Atrial Fibrillation In Specific Populmentioning

confidence: 99%

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population

Nielsen

Lin

Figueiredo

et al. 2020

Journal of Arrhythmia

View full text Add to dashboard Cite

show abstract

“…Such a window current also contributes to the AP repolarization phase. In addition, late and/or window I Na may also affect pacemaker activity of sinoatrial nodal (SAN) cells ( 8 , 10 ) and excitability ( 16 ). Upon return to hyperpolarized potentials, i.e., during or following the AP repolarization, Na V 1.5 channels can quickly recover from inactivation ( 14 ).…”

Section: Cardiac Disorders Associated With Scn5a Mmentioning

confidence: 99%

“…In familial forms of AF, both SCN5A loss-of-function and gain-of-function mutations have been identified ( 20 ). The gain-of-function can be due to various gating changes including negative shifts in voltage dependence of activation, positive shifts in voltage dependence of inactivation, slower current inactivation, and faster recovery from inactivation [see ( 16 ), and primary references cited therein]. Loss-of-function can be the consequence of reduced I Na density ( 21 ) or of a negative shift in voltage dependence of inactivation ( 22 ).…”

Section: Cardiac Disorders Associated With Scn5a Mmentioning

confidence: 99%

Disease Modifiers of Inherited SCN5A Channelopathy

Verkerk

Amin

Remme

2018

Front. Cardiovasc. Med.

Self Cite

View full text Add to dashboard Cite

To date, a large number of mutations in SCN5A, the gene encoding the pore-forming α-subunit of the primary cardiac Na+ channel (NaV1.5), have been found in patients presenting with a wide range of ECG abnormalities and cardiac syndromes. Although these mutations all affect the same NaV1.5 channel, the associated cardiac syndromes each display distinct phenotypical and biophysical characteristics. Variable disease expressivity has also been reported, where one particular mutation in SCN5A may lead to either one particular symptom, a range of various clinical signs, or no symptoms at all, even within one single family. Additionally, disease severity may vary considerably between patients carrying the same mutation. The exact reasons are unknown, but evidence is increasing that various cardiac and non-cardiac conditions can influence the expressivity and severity of inherited SCN5A channelopathies. In this review, we provide a summary of identified disease entities caused by SCN5A mutations, and give an overview of co-morbidities and other (non)-genetic factors which may modify SCN5A channelopathies. A comprehensive knowledge of these modulatory factors is not only essential for a complete understanding of the diverse clinical phenotypes associated with SCN5A mutations, but also for successful development of effective risk stratification and (alternative) treatment paradigms.

show abstract

Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation

Cited by 33 publications

References 17 publications

SCN5A mutation identified in a patient with short‐coupled variant of torsades de pointes

SCN5A mutation identified in a patient with short‐coupled variant of torsades de pointes

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population

Disease Modifiers of Inherited SCN5A Channelopathy

Contact Info

Product

Resources

About