Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

Watanabe, Hiroshi; Koopmann, Tamara T.; Scouarnec, Solena Le; Yang, Tao; Ingram, Christiana R.; Schott, Jean‐Jacques; Demolombe, Sophie; Probst, Vincent; Anselme, F.; Escande, Denis; Wiesfeld, Ans C.P.; Pfeufer, Arne; Kääb, Stefan; Wichmann, Hans; Hasdemir, Can; Aizawa, Yoshifusa; Wilde, Arthur A.M.; Roden, Dan M.; Bezzina, Connie R.

doi:10.1172/jci33891

Cited by 266 publications

(327 citation statements)

References 57 publications

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“…Several pathogenic variations in three genes (SCN1B, SCN2B, SCN3B) encoding β subunits of the Na v 1.5 sodium channel have been discovered to modify the function of the channel (increasing or decreasing I Na ). [54][55][56] SCN10A, a gene encoding the neuronal sodium channel Na v 1.8, has been shown to modulate SCN5A expression and the electrical function of the heart. 57 Pathogenic variations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) reduce both the surface membrane expression and the inward I Na of Na v 1.5.…”

Section: Genetic Basismentioning

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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Section: Genetic Basismentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

128

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“…The gene spans 9.8 kb at chromosome 19q13.1 and is composed of six exons [Makita et al, 1994;Watanabe et al, 2008]. The SCN1B gene is translated into two isoforms: b1, which is a 218 amino acid, and b1b, which is a 268 amino acid protein.…”

Section: Brs5-mutations In Scn1bmentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

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“…In “gain-of-function” mutations, an increase in the persistent late I Na during the action potential plateau, rather than in peak I Na is typically thought to be responsible for the type 3 long QT syndrome (LQT3) phenotype whereby repolarization is delayed and the QT interval is prolonged on the surface electrocardiogram (ECG) [5]. In contrast, “loss-of-function” mutations in SCN5A cause a decrease in peak I Na , leading to phenotypes including Brugada syndrome (BrS), cardiac conduction disturbance (CCD), congenital sick sinus syndrome (SSS), atrial standstill, AV block, sudden infant syndrome, and familial atrial fibrillation [3,6]. Some SCN5A mutations have also been found to yield mixed clinical and/or biophysical phenotypes [7,8].…”

Section: Introductionmentioning

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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Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

Cited by 266 publications

References 57 publications

Brugada syndrome: clinical and genetic findings

Brugada syndrome: clinical and genetic findings

The genetic basis of Brugada syndrome: A mutation update

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

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