&lt;i&gt;SCN5A &lt;/i&gt;Mutations Associated With Overlap Phenotype of Long QT Syndrome Type 3 and Brugada Syndrome

Nakaya, Haruaki

doi:10.1253/circj.cj-14-0319

Cited by 12 publications

(11 citation statements)

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“…Our study illuminated the abnormality in AP pro les of BrS-CMs, which is in line with previous studies (25). The BrS-CMs also presented a prolonged AP duration, which seems to be an overlapping feature of long QT type 3 and BrS (26) (27). Moreover, BrS-CMs exhibited multiple abnormal calcium-related activities, including EAD-like and DAD-like events, which are thought to be a surrogate for polymorphic VT (28,29).…”

Section: Electrophysiological Abnormalities Caused By Na V 15 Gene Vsupporting

confidence: 91%

Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

Zhu

Wang

Cui

et al. 2020

Preprint

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Background: Brugada syndrome (BrS) is an autosomal dominant disorder that causes a high predisposition to sudden cardiac death. Several genes have been reported to be associated with BrS. Considering that the heterogeneity in clinical manifestations may result from genetic variations, the application of patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs) may help to reveal cell phenotype characteristics resulting from different genetic backgrounds. The present study was to compare the structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and evaluate the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes.Methods: Two BrS patient-specific iPS cell lines were constructed that carried missense mutations in SCN5A and SCN1B. One iPS cell line from a healthy volunteer was used as a control. The differentiated cardiomyocytes from the three groups were evaluated by flow cytometry, immunofluorescence staining, electron microscopy, as well as calcium transient and patch clamp analyses to assess different pathological phenotypes. Finally, we evaluated the drug responses to varying concentrations of quinidine by measuring the action potential.Results: Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration and varying degrees of decreased Vmax, but no structural difference was observed. After applying different concentrations of quinidine, the disease-specific groups and the control group had a downward trend in maximal upstroke velocity, resting membrane potential and action potential amplitude, and exhibited prolonged action potential duration without increasing incidence of arrhythmic events.Conclusion: Both patient-specific iPSC-CMs recapitulated the BrS phenotype at the cellular level. Although the SCN5A variation led to a markedly lower sodium current than what was observed with the SCN1B variation, their responses to quinidine were quite similar. The present study provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.

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Section: Electrophysiological Abnormalities Caused By Na V 15 Gene Vsupporting

confidence: 91%

Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

Zhu

Wang

Cui

et al. 2020

Preprint

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“…89 Several subtypes of LQTS have been reported, such as type III (LQTS-3) caused by pathogenic variations in the SCN5A gene and responsible for nearly 10% of all LQTS cases. 90 Therefore, SCN5A pathogenic variants associated with LQTS induce gain-of-function in contrast to pathogenic variants associated with BrS (inducing loss-of-function). It remains to be understood how a pathogenic variation in the same gene may induce almost opposite electrical defects.…”

Section: Long Qt Syndrome Type IIImentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

128

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Review ARticleMore than 20 years ago, eight individuals were resuscitated from sudden cardiac death (SCD) caused by documented ventricular fibrillation (VF); all showed a characteristic ST segment elevation in the right precordial leads and a structurally normal heart. 1 In 1996, the term "Brugada syndrome" (BrS) was used to describe what was previously known as "right bundle branch block, persistent ST segment elevation, and sudden death syndrome. " 2 A year later, BrS was reported to be the same disease as sudden unexplained nocturnal death syndrome (SUNDS). In other countries, BrS has different names: Lai Tai (Thailand), Pokkuri (Japan), and Bangungut (Philippines). Currently, the prevalence of BrS is estimated at ~3-5 in 10,000 people, and it is higher in young men of Southeast Asian origin. It is the main cause of death among young healthy men in Southeast Asia. 3 Recent reports suggest that BrS could be responsible for 4% of all SCD and up to 12% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, at a mean age of 41 years, and it is 8-to 10-times more frequent in males. Frequently, sudden death can be the first manifestation of the disease. 4 In 1998, the genetic basis of BrS was established when the sodium channel protein type V subunit α gene (SCN5A), which encodes the α-subunit of the voltage-gated Na v 1.5 cardiac sodium channel responsible for regulating rapid sodium current (I Na ), was associated with the disease. 5 Currently, BrS is recognized as a rare, inherited cardiac channelopathy caused by an alteration of ionic currents that leads to ventricular arrhythmias and SCD. It is clinically characterized by ST segment elevation in leads V1-V3 of the electrocardiogram, but incomplete penetrance and variable expressivity confound the diagnosis. 6 Despite the identification of 18 associated genes, 65-70% of clinically diagnosed cases remain without an identifiable genetic cause. 4 CLINICAL DIAGNOSIS Diagnostic criteriaThe clinical diagnosis of BrS requires the identification of the ST segment elevation in the right precordial leads at baseline or after the use of sodium blockers. Three different electrocardiographic (ECG) patterns can be often observed in families with BrS: type I, which consists of a coved-type ST segment elevation greater than 2 mm followed by a descending negative T wave in at least two right precordial leads (V1 to V3); type II ST elevation, saddleback-shaped patterns with a high initial increase followed by an ST elevation greater than 2 mm; and saddleback-shaped patterns with a high initial increase followed by an ST elevation less than 2 mm (Figure 1). The second Brugada Consensus Report proposed that only type I is diagnostic for BrS 7 and, in 2013, it was proposed that a definitive diagnosis of BrS considers both spontaneous type I pattern and a provoked type I pattern (with a baseline type II or III pattern) in at least one right precordial lead (V1 or V2). 8 The diagnosis of BrS is currently accepted in those patients ...

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“…Recently, Kanter et al [25] reported ventricular arrhythmias and intra-ventricular conduction delays in young children due to loss-of-function sodium and/or calcium channelopathies. Other recently reported SCN5A mutation-related overlap syndromes included LQT3 and dilated cardiomyopathy [26], LQT3 and early-onset lone atrial fibrillation [27], LQT3 and Brugada syndrome [28], and Brugada syndrome, conduction disease and atrial flutter [29 & ].…”

Section: Scn5a Overlap Syndromementioning

confidence: 99%