Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population

Wang, Pengyun; Yang, Qinbo; Wu, Xiaofen; Yang, Yanzong; Shi, Lisong; Wang, Chuchu; Wu, Gang; Xia, Yunlong; Yang, Bo; Zhang, Rongfeng; Xu, Chengqi; Cheng, Xiang; Li, Sisi; Zhao, Yuanyuan; Fu, Fenfen; Liao, Yuhua; Fang, Fang; Chen, Qiuyun; Tu, Xin; Wang, Qing Kenneth

doi:10.1016/j.bbrc.2010.06.042

Cited by 74 publications

(51 citation statements)

References 25 publications

(41 reference statements)

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“…Watanabe et al 70 found two nonsynonymous loss-of-function mutations in SCN1B and two in SCN2B in a cohort of 480 AF patients. Wang et al 71 found a lossof-function mutation in SCN3B in another lone AF cohort. Moreover, Olesen et al 72 identified three non-synonymous mutations in SCN3B, which displayed a loss-of-function effect in the sodium current.…”

Section: Sodium Channel Mutationsmentioning

confidence: 95%

Atrial fibrillation: the role of common and rare genetic variants

Olesen

Nielsen

Haunsø³

et al. 2013

Eur J Hum Genet

102

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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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Section: Sodium Channel Mutationsmentioning

confidence: 95%

Atrial fibrillation: the role of common and rare genetic variants

Olesen

Nielsen

Haunsø³

et al. 2013

Eur J Hum Genet

102

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“…Genome-wide linkage analysis with polymorphic genetic markers mapped multiple susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in 2 genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (15)(16)(17)(18)(19)(20)(21). Additionally, a genetic scan of candidate genes revealed a long list of AF associated genes, including KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNA5, SCN5A, SCN1B, SCN2B, SCN3B, NPPA, GJA1 and GJA5 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Nevertheless, AF is a genetically heterogeneous disease and the genetic determinants for AF in a large proportion of patients remain unclear.…”

Section: Introductionmentioning

confidence: 99%

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

Wang

Huang

Wang

et al. 2012

International Journal of Molecular Medicine

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Abstract. Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with significantly increased morbidity and mortality. Cumulative evidence highlights the importance of genetic defects in the pathogenesis of AF. However, AF is of remarkable heterogeneity and the genetic determinants of AF in a vast majority of patients remain illusive. In this study, the coding exons and splice junctions of the GATA5 gene, which encodes a zinc-finger transcription factor essential for normal cardiogenesis, were sequenced in 118 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA5 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.W200G, was identified in a family with AF inherited as an autosomal dominant trait. The mutation was absent in 200 control individuals and the altered amino acid was completely conserved evolutionarily across species. Functional analysis showed that the mutation of GATA5 was associated with a significantly decreased transcriptional activity. These findings provide novel insight into the molecular mechanism involved in AF, suggesting potential implications for the early prophylaxis and genespecific therapy of AF.

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“…However, recently, Wang and colleagues sequenced 477 patients with AF for mutations in SCN3B and identified a missense mutation in SCN3B (c.389CϾT resulting in p.A130V, located in the distal portion of the amino terminus) in one patient. 49 When coexpressed with Na v 1.5, the mutant ␤3-subunit resulted in a decrease in peak I Na density and no gating changes. Surprisingly, Western blot analysis revealed that the mutation did not affect the surface expression of Na v 1.5.…”

Section: Wilde and Brugada Cardiac Disease And Subunits Of The Sodiummentioning

confidence: 99%

“…46 In addition, mutations in the ␤-subunits SCN1B, SCN2B, and SCN3B have been associated with AF by decreasing I Na . [47][48][49] It is hypothesized that loss of I Na function leads to altered atrial conduction parameters, increased fibrosis, and associated structural abnormalities (including increased diastolic ventricular pressure in the setting of dilated cardiomyopathy with subsequent enlargement of the atria), that all act together to cause AF. …”

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confidence: 99%

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Wilde

Brugada

2011

Circulation Research

189

134

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Abstract:Variations in the gene encoding for the major sodium channel (Na v 1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Of equal importance are variations in genes encoding for various subunits and regulatory proteins interacting with the ␣-subunit Na v 1.5 and modifying its function. Based on detailed studies of genotype-phenotype relationships in these disease entities, on detailed studies of the basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels and their interacting proteins), and on attempts to integrate the obtained knowledge, the past 15 years has witnessed an explosion of knowledge about these disease entities. (Circ Res. 2011;108:884-897.) Key Words: sodium channel Ⅲ arrhythmias Ⅲ sudden cardiac death I nitially based on genetic studies in the mid-1990s, the SCN5A gene, encoding the major sodium channel (Na v 1.5) in the heart, has been unmasked as an important player in a number of primary arrhythmia syndromes. Indeed, sodium channel dysfunction resulting from mutation-based alterations in channel function is associated with the long-QT syndrome (LQTS) (type 3), 1 the syndrome of right precordial ST elevation, ie, Brugada syndrome (BrS), 2 (progressive) cardiac conduction disease (CCD), 2,3 sinus node dysfunction, 4 atrial fibrillation (AF), 5 atrial standstill, 6,7 and dilated cardiomyopathy. 8 Because many of these diseases associate with sudden death in young individuals with a structurally normal heart, potentially causal SCN5A variants have also been identified in sudden infant or sudden unexplained death syndrome (SIDS/SUDS). 9,10 Detailed descriptions of the clinical (patients) and basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels) have profoundly increased our knowledge about these disease entities and about the role of the sodium channel and its interaction with various subunits. Indeed, besidesOriginal received September 2, 2010; resubmission received December 8, 2010; revised resubmission received January 13, 2011; accepted January 28, 2011. In December 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days. ␤-subunits (␤1 to ␤4), the ␣-subunit Na v 1.5 also interacts with several regulatory proteins, of which, more recently, malfunction resulting from disease-causing variants in their encoding genes has been shown to underlie comparable phenotypes. This article aims to review the existing knowledge of the basic and clinical aspects of sodium channel related diseases. It begins with a review of sodium channel function in normal and abnormal conditions that is followed by a description of the diverse clinical phenotypes. The Cardia...

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Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population

Cited by 74 publications

References 25 publications

Atrial fibrillation: the role of common and rare genetic variants

Atrial fibrillation: the role of common and rare genetic variants

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

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