Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

Xie, Wei; Chang, Cheng; Xu, Ying‐Jia; Li, Ruogu; Qu, Xinkai; Fang, Wei-Yi; Liu, Xu; Yang, Yi‐Qing

doi:10.6061/clinics/2013(06)09

Cited by 44 publications

(30 citation statements)

References 37 publications

(34 reference statements)

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“…Similarly, mutations in other cardiac transcriptional factor genes, such as GATA4, GATA5, NKX2-5 and PITX2c, were also associated with atrial fibrillation (21)(22)(23)(46)(47)(48)(49)(50)(51)(52)(53). These observations support the hypothesis that a subset of atrial fibrillation may have developmental origin.…”

Section: Subject Informationsupporting

confidence: 74%

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

Zhao

Fang

et al. 2014

International Journal of Molecular Medicine

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Abstract. Dilated cardiomyopathy (DCM), the most prevalent form of primary heart muscle disease, is the third most common cause of heart failure and the most frequent reason for cardiac transplantation. Mounting evidence has demonstrated that genetic risk factors are crucial in the pathogenesis of DCM. However, DCM is genetically heterogeneous, and the genetic basis of DCM in a large majority of cases remains unclear. In the current study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 140 unrelated patients with DCM, and two novel heterozygous mutations, p.C447Y and p.H475R, were identified in two index patients with DCM, respectively. Analysis of the pedigrees showed that in each family the mutation co-segregated with DCM transmitted in an autosomal-dominant pattern, with complete penetrance. The missense mutations were absent in 400 control chromosomes and predicted to be disease-causing by MutationTaster or probably damaging by PolyPhen-2. The alignment of multiple GATA6 proteins across species revealed that the altered amino acids were completely conserved evolutionarily. The functional assays showed that the mutated GATA6 proteins were associated with significantly reduced transcriptional activation in comparison with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA6 loss-of-function mutations with enhanced susceptibility to familial DCM, which provides novel insight into the molecular mechanism of DCM and suggests potential implications for the antenatal prophylaxis and allele-specific treatment of DCM.

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Section: Subject Informationsupporting

confidence: 74%

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

Zhao

Fang

et al. 2014

International Journal of Molecular Medicine

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“…The absence of Tbx3 and Isl1 expression, which are also positive regulators of SAN development, in the PV myocardium (Christoffels et al, 2010; our unpublished data) supports a unique role for Shox2 in controlling a pacemaker program independently of Tbx3 and Isl1. However, the presence of Nkx2-5 prevents the adoption of pacemaker function in the PV myocardium, providing an explanation for the association of AF with NKX2-5 mutations in humans Wang et al, 2014b;Xie et al, 2013). We therefore propose a seesaw model for the function of Shox2-Nkx2-5 antagonism in the regulation of cell fate during venous pole development (Fig.…”

Section: Discussion Developmental Origin Of the Pv Myocardiummentioning

confidence: 99%

“…The PV myocardium is also positive for HNK-1 and CCS-lacZ, two putative cardiac conduction system (CCS) markers (Douglas et al, 2011;Jongbloed et al, 2004;Wenink et al, 2000). The association of mutations in NKX2-5 with AF patients Xie et al, 2013), and the switch of the PV myocardium to an Hcn4…”

Section: Introductionmentioning

confidence: 99%

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

et al. 2015

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In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. The genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-like myocardial identity in the PV, is lacking in the SAN. Here we present evidence that in mice Shox2 antagonizes the transcriptional output of Nkx2-5 in the PV myocardium and in a functional Nkx2-5 + domain within the SAN to determine cell fate. Shox2 deletion in the Nkx2-5 + domain of the SAN caused sick sinus syndrome, associated with the loss of the pacemaker program. Explanted Shox2 + cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surrounding Shox2 − cells. Shox2 deletion led to Hcn4 ablation in the developing PV myocardium. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in the PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. A similar mechanism is also adopted in differentiated embryoid bodies. We found that Shox2 interacts with Nkx2-5 directly, and discovered a substantial genomewide co-occupancy of Shox2, Nkx2-5 and Tbx5, further supporting a pivotal role for Shox2 in the core myogenic program orchestrating venous pole and pacemaker development.

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“…Implicated genes include those encoding connexin 40, GJA5 [7, 67–69], the transcription factor gene NKX2.5 [70, 71], and the LMNA gene[72]. Genes involved in the renin-angiotensin-aldosterone pathway, including the angiotensin converting enzyme, angiotensin gene promoter and angiotensinogen[73–76], have also been associated with AF.…”

Section: Polygenic Non-familial Common Afmentioning

confidence: 99%

Genomics of Atrial Fibrillation

Gutiérrez

Chung

2016

Curr Cardiol Rep

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Atrial fibrillation (AF) is a common clinical arrhythmia that appears to be highly heritable, despite representing a complex interplay of several disease processes that generally do not manifest until later in life. In this manuscript we will review the genetic basis of this complex trait established through studies of familial AF, linkage and candidate gene studies of common AF, genome wide association studies (GWAS) of common AF, and transcriptomic studies of AF. Since AF is associated with a five-fold increase in the risk of stroke, we also review the intersection of common genetic factors associated with both of these conditions. Similarly, we highlight the intersection of common genetic markers associated with some risk factors for AF, such as hypertension and obesity, and AF. Lastly, we describe a paradigm where genetic factors predispose to the risk of AF, but which may require additional stress and trigger factors in older age to allow for the clinical manifestation of AF.

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Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

Cited by 44 publications

References 37 publications

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

Genomics of Atrial Fibrillation

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