<i>KCNE5</i>
            (
            <i>KCNE1L</i>
            ) Variants Are Novel Modulators of Brugada Syndrome and Idiopathic Ventricular Fibrillation

Ohno, Seiko; Zankov, Dimitar P.; Ding, Wei‐Guang; Itoh, Hideki; Makiyama, Takeru; Doi, Takahiro; Shizuta, Satoshi; Hattori, Takashi; Miyamoto, Akashi; Naiki, Nobu; Hancox, Jules C.; Matsuura, Hiroshi; Horie, Minorou

doi:10.1161/circep.110.959619

Cited by 118 publications

(87 citation statements)

References 34 publications

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“…63 Interestingly, the KCNE5 gene is located on the X chromosome, adding a new pattern of inheritance for BrS. 64 Hence, pathogenic variations in KCNE5 cause a gain-of-function effect on I to current gradients. Similar is the role of adenosine triphosphate (ATP)-sensitive potassium cardiac channels, which consist of the potassium inward-rectifying channel subunit (Kir6.1), encoded by KCNJ8, 65 and sulfonylurea receptor subunit 2A (SUR2A), encoded by the ATP-binding cassette, subfamily C member 9 (ABCC9) gene.…”

Section: Genetic Basismentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

125

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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

125

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“…18 Mutations in genes encoding the α1-(CACNA1c) and β2b-(CACNB2b) subunits of the L-type cardiac calcium (Ca 2+ ) channel leading to a decrease of the ICa current, result in a combined BS/short QT syndrome. 19 Other genes recently reported to be linked to the syndrome are: SCN1B (encoding for β1-and β1b-subunits, auxiliary function-modifying subunits of the cardiac Na + channel, resulting in a decrease of the INa current by affecting the Na + channel trafficking; 20 KCNE3 21 (encoding MiRP2, a protein that decreases the potassium (K + ) transient outward current (Ito) current by interacting with channel Kv4.3, resulting in an increase of Ito magnitude and density; 21 SCN3B (which encodes for the β3-subunit of the Na + cardiac channel, and leading to a loss of function of the Na + cardiac channel also cause B BERNE P et al 23 (mutations in this gene cause INa reduction by impairing the trafficking of the cardiac Na + channel to the cell membrane); KCNE5 24 and KCND3 25 (mutations in both genes leading to an increase of the Ito current have been linked to BS). Each of the these 9 genes is responsible for less than 1% of reported cases of BS.…”

Section: Genetic Basis Of Bsmentioning

confidence: 99%

Brugada Syndrome 2012

Berne

Brugada

2012

Circ J

161

140

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“…Inheritance is autosomal dominant with incomplete and often low penetrance and a substantial male predominance. One attractive hypothesis to explain incomplete penetrance in BrS is the existence of genetic modifiers that may be common variants in SCN5A or other genes (89)(90)(91).…”

Section: Figurementioning

confidence: 99%

Molecular and genetic basis of sudden cardiac death

George

2013

J. Clin. Invest.

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The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

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KCNE5 ( KCNE1L ) Variants Are Novel Modulators of Brugada Syndrome and Idiopathic Ventricular Fibrillation

Abstract: KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.

Cited by 118 publications

References 34 publications

Brugada syndrome: clinical and genetic findings

Brugada syndrome: clinical and genetic findings

Brugada Syndrome 2012

Molecular and genetic basis of sudden cardiac death

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