Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

Yang, Yi‐Qing; Li, Jun; Lin, Xiaoping; Yang, Yanzong; Hong, Kui; Wang, Lei; Liu, Jinqiu; Li, Li; Yan, Dinghong; Liang, Dandan; Xiao, Junjie; Jin, Hongmei; Wu, Jie; Zhang, Yangyang; Chen, Yihan

doi:10.1038/jhg.2009.26

Cited by 104 publications

(65 citation statements)

References 36 publications

(33 reference statements)

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“…44,45 The second one being that a prolonged ERP enhances the propensity for early afterdepolarization (EAD) and thereby, increasing the susceptibility to AF. 46 For a general introduction to cAP and involved ion channels, please see Nattel 44 and/or ShiroshitaTakeshita et al 47 In the following, current knowledge about rare variants in the individual genes and their possible involvement in the pathogenesis of AF will be presented.…”

Section: The Role Of Rare Genetic Variantsmentioning

confidence: 99%

“…A number of mutations have since then been identified (see Table 2). 46,[64][65][66] The ABCC9 gene encodes the SUR2A K ATP channel subunit involved in maintaining electrical stability under stress, including adrenergic challenge. Olson et al 67 identified a missense mutation in the ABCC9 gene in a female case with early-onset AF originating from the vein of Marshall.…”

Section: Potassium Channel Mutationsmentioning

confidence: 99%

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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: The Role Of Rare Genetic Variantsmentioning

confidence: 99%

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

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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“…Both gain-of-function and loss-of-function mutations in genes encoding potassium and sodium channel subunits have been reported to underlie familial AF. [2][3][4][5][6][7][8][9][11][12][13]25,26,[29][30][31]43 Gain-offunction potassium channel mutations are predicted to influence AF by shortening the atrial effective refractory period, an effect that would be predicted to promote atrial re-entry. 44 Loss-of-function potassium channel mutations are predicted to promote triggered activity in the atrium, which is also an important contributor to the genesis of AF.…”

Section: Historical Perspectivementioning

confidence: 99%

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

Mahida

2014

Arrhythmia &Amp; Electrophysiology Review

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Linkage analysis and candidate-gene sequencing have identified multiple mutations in monogenic AF families and isolated AF cases. 2-31Linkage analysis involves performing genotyping of markers distributed AbstractAtrial fibrillation (AF) is an arrhythmia with a genetic basis. Over the past decade, rapid advances in genotyping technology have revolutionised research regarding the genetic basis of AF. While AF genetics research was previously largely restricted to familial forms of AF, recent studies have begun to characterise the genetic architecture underlying the form of AF encountered in everyday clinical practice. These discoveries could have a significant impact on the management of AF. However, much work remains before genetic findings can be translated to clinical practice. This review summarises results of studies in AF genetics to date and discusses the potential implications of these findings in clinical practice. KeywordsAtrial fibrillation, genetics, familial AF, linkage analysis, candidate gene association studies, genome-wide association studies, risk stratification Disclosure: The author has no conflicts of interest to declare.

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Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

Cited by 104 publications

References 36 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

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

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