Gain-of-function mutation S422L in the KCNJ8-encoded cardiac KATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes

Medeiros-Domingo, Argelia; Tan, Bi Hua; Crotti, Lia; Tester, David J.; Eckhardt, Lee L.; Cuoretti, Alessandra; Kroboth, Stacie; Song, Chunhua; Zhou, Qing; Kopp, Douglas E.; Schwartz, Peter J.; Makielski, Jonathan C.; Ackerman, Michael J.

doi:10.1016/j.hrthm.2010.06.016

Cited by 248 publications

(176 citation statements)

References 40 publications

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“…The WT- or N406K-SCN5A cDNA was transiently co-transfected with pMaxGFP cDNA, at a ratio of 5:1, into HEK293 cells with Superfect (Qiagen, Valencia, CA) following manufacturer’s recommended protocol [13,14]. After 3–5 hours of incubation, the transfection reagent-DNA mixture was replaced with 3 ml of normal culture medium with or without 500 μM mexiletine, and the cells were incubated at 37°C for 48 hours.…”

Section: Methodsmentioning

confidence: 99%

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

Channels

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Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. Methods and Results: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. Conclusion: SCN5A-N406K channel displays both “gain-of-function” in late INa and “loss-of-function” in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both “gain-of-function” and “loss-of-function” of the mutant sodium channel.

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Section: Methodsmentioning

confidence: 99%

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

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“…61 In a previous study, the mutation was shown to display a gain-of-function effect. 62 The KCNA5 gene encodes the atria-specific K v 1.5 channel responsible for the ultra-rapid delayed rectifier potassium current, I Kur , involved in cardiac repolarization. Olson et al 63 identified a nonsense mutation in a familial case of AF.…”

Section: Potassium Channel Mutationsmentioning

confidence: 99%

Atrial fibrillation: the role of common and rare genetic variants

Olesen

Nielsen

Haunsø³

et al. 2013

Eur J Hum Genet

105

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Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1-2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain-and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF. Furthermore, all rare variants reported to be associated with AF were systematically searched for in the Exome Sequencing Project Exome Variant Server.

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“…9,14 Mutations in glycerol-3-phophate dehydrogenase 1-like enzyme gene (GPD1L, BrS2), SCN1B (β1-subunit of Na channel, BrS5), KCNE3 (MiRP2; BrS6), SCN3B (β3-subunit of Na channel, BrS7), KCNJ8 (BrS8), and KCND3 (BrS10) are more rare. [10][11][12]15,16,34 These genetic defects cause a loss of function of I Na or I Ca , or a gain of function of I to . These and other genetic variants may give rise to subclinical forms of BrS, that can predispose to acquired forms of BrS developing following administration of antidepressants such as amitriptyline and pharmacological agents with similar actions.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations leading to loss of function in I Na and I Ca , as well as those giving rise to a gain of function in I to , have been identified as genetic causes of BrS. [6][7][8][9][10][11][12][13][14][15][16][17] BrS has thus far been associated with mutations in 11 different genes.…”

Section: Introductionmentioning

confidence: 99%

Ionic and Cellular Mechanisms Underlying the Development of Acquired Brugada Syndrome in Patients Treated with Antidepressants

Minoura¹,

Diego²,

Barajas-Martínez³

et al. 2011

J Arrhythmia

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Introduction-Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established.

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Gain-of-function mutation S422L in the KCNJ8-encoded cardiac KATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes

Cited by 248 publications

References 40 publications

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Atrial fibrillation: the role of common and rare genetic variants

Ionic and Cellular Mechanisms Underlying the Development of Acquired Brugada Syndrome in Patients Treated with Antidepressants

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