Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing

Li, Qiuju; Huang, Hai; Liu, Gele; Lam, Khanh; Rutberg, Julie; Green, Martin S.; Birnie, David H.; Lemery, Robert; Chahine, Mohamed; Gollob, Michael H.

doi:10.1016/j.bbrc.2009.01.052

Cited by 108 publications

(68 citation statements)

References 33 publications

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“…a second study from our group involving a mother and son with lone af identified a lys1493arg mutation involving a highly conserved residue within the diii-iv linker located 6 amino acids downstream from the fast inactivation motif of sodium channels. 46 Biophysical studies demonstrated a significant positive shift in the voltage dependence of inactivation and a large ramp current near resting membrane potential, consistent with a gain of function. When expressed in hl-1 atrial cardiomyocytes, enhanced cellular excitability was observed in the form of spontaneous action potential depolarizations and a lower threshold for action potential firing as compared to wild-type cells.…”

Section: Connexinsmentioning

confidence: 70%

“…the depolarizing shift in steady-state inactivation increases the probability that the channel will be in the open conformation and capable of conducting current. 46 this alteration in the gating of the nav1.5-mediated current will presumably result in a predisposition for cells to reach threshold potential and fire, consistent with enhanced automaticity. this increase in focal discharges has the potential to serve as the trigger for af.…”

Section: Connexinsmentioning

confidence: 99%

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A Contemporary Review on the Genetic Basis of Atrial Fibrillation

Roberts¹,

Gollob

2014

Methodist DeBakey Cardiovascular Journal

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Atrial fibrillation is the most common sustained cardiac arrhythmia, and affected individuals suffer from increased rates of heart failure, stroke, and death. Despite the enormous clinical burden that it exerts on patients and health care systems, contemporary treatment strategies have only modest efficacy that likely stems from our limited understanding of its underlying pathophysiology. Epidemiological studies have provided unequivocal evidence that the arrhythmia has a substantial heritable component. Subsequent investigations into the genetics underlying atrial fibrillation have suggested that there is considerable interindividual variability in the pathophysiology characterizing the arrhythmia. This heterogeneity may partly account for the poor treatment efficacy of current therapies. Subdividing atrial fibrillation into mechanistic subtypes on the basis of genotype illustrates the heterogeneous nature of the arrhythmia and may ultimately help guide treatment strategies. A pharmacogenetic approach to the management of atrial fibrillation may lead to dramatic improvements in treatment efficacy and improved patient outcomes

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Section: Connexinsmentioning

confidence: 70%

Section: Connexinsmentioning

confidence: 99%

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

Roberts¹,

Gollob

2014

Methodist DeBakey Cardiovascular Journal

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“…Both gain-of-function and loss-of-function mutations in genes encoding potassium and sodium channel subunits have been reported to underlie familial AF. [2][3][4][5][6][7][8][9][11][12][13]25,26,[29][30][31]43 Gain-offunction potassium channel mutations are predicted to influence AF by shortening the atrial effective refractory period, an effect that would be predicted to promote atrial re-entry. 44 Loss-of-function potassium channel mutations are predicted to promote triggered activity in the atrium, which is also an important contributor to the genesis of AF.…”

Section: Historical Perspectivementioning

confidence: 99%

“…8 Gain-of-function sodium channel mutations are predicted to promote triggered activity. 25 Loss-of-function sodium channel mutations are predicted to shorten the wavelength of an impulse circulating around a re-entry circuit. 45 The potential mechanistic links between non-ion channel mutations and AF pathogenesis are less clearly understood.…”

Section: Historical Perspectivementioning

confidence: 99%

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

Mahida

2014

Arrhythmia &Amp; Electrophysiology Review

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Linkage analysis and candidate-gene sequencing have identified multiple mutations in monogenic AF families and isolated AF cases. 2-31Linkage analysis involves performing genotyping of markers distributed AbstractAtrial fibrillation (AF) is an arrhythmia with a genetic basis. Over the past decade, rapid advances in genotyping technology have revolutionised research regarding the genetic basis of AF. While AF genetics research was previously largely restricted to familial forms of AF, recent studies have begun to characterise the genetic architecture underlying the form of AF encountered in everyday clinical practice. These discoveries could have a significant impact on the management of AF. However, much work remains before genetic findings can be translated to clinical practice. This review summarises results of studies in AF genetics to date and discusses the potential implications of these findings in clinical practice. KeywordsAtrial fibrillation, genetics, familial AF, linkage analysis, candidate gene association studies, genome-wide association studies, risk stratification Disclosure: The author has no conflicts of interest to declare.

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“…In recent years, familial forms of atrial fibrillation have been explored using sophisticated molecular approaches. One such study demonstrated a causative role mutation in the potassium channels responsible for the slow re-polarization of atrial myocytes (KCNQ1, KCNE2, KCNJ2) [320][321][322]. However, the vast majority of atrial fibrillation is sporadic and non-familial.…”

Section: Previous Work To Replicate Cardiac Diseases Using Ipsc Cell mentioning

confidence: 99%

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

Jambi¹,

Ye²,

Gollob³

et al. 2013

Canadian Journal of Cardiology

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Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing

Cited by 108 publications

References 33 publications

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

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