Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Shi, Haifeng; Yang, Jiao; Wang, Qian; Li, Ruogu; Xu, Ying‐Jia; Qu, Xinkai; Fang, Wei-Yi; Liu, Xu; Yang, Yi‐Qing

doi:10.3892/mmr.2012.1252

Cited by 33 publications

(16 citation statements)

References 60 publications

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“…AF, the most common form of sustained cardiac arrhythmia, is characterized by uncoordinated atrial activation and chaotic electrical activity, with consequent deterioration of atrial mechanical function (19). Using the in vitro rat AMC culture and rapid pacing model, the present study demonstrated that rapid pacing shortened the APD and downregulated the expression levels of LTCC and potassium channels.…”

Section: Discussionmentioning

confidence: 51%

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

Wang

Zhu

et al. 2016

Molecular Medicine Reports

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Remodeling of atrial electrophysiology and structure is the primary feature of atrial fibrillation (AF). Evidence suggests that abnormalities in the expression levels of embryological cardiovascular development‑associated transcription factors, including Nkx2.5, are crucial for the development of AF. Rat atrial myocardial cells (AMCs) in culture dishes were placed in an electric field and stimulated. Transmission electron microscopy was used to observe the ultrastucture prior to and following rapid pacing. The action potential durations and effective refractory periods were measured. RT‑PCR and western blotting were performed to investigate the effect of rapid pacing on the expression levels of ion channel and nuclear proteins in AMCs. Nkx2.5 short interfering RNA (siRNA) transfection was performed. Through this in vitro rat AMC culture and rapid pacing model, it was demonstrated that rapid pacing shortened the action potential and downregulated the expression levels of L‑type calcium and potassium channels. Expression levels of Nkx2.5 and cardiac ankyrin repeat protein (CARP) were significantly upregulated by rapid pacing at the mRNA and protein levels. siRNA‑mediated Nkx2.5 silencing attenuated the rapid pacing‑induced downreglation of ion channel levels. These results suggest that the Nkx2.5/CARP signaling pathway contributes to the early electrical remodeling process of AF.

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Section: Discussionmentioning

confidence: 51%

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

Wang

Zhu

et al. 2016

Molecular Medicine Reports

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“…Both somatic and germ-line mutations of Cx40 have been identified in patients with lone AF [14–16, 29]. These mutations apparently contribute to AF by reducing the abundance of functional Cx40.…”

Section: Discussionmentioning

confidence: 99%

Connexin40 abnormalities and atrial fibrillation in the human heart

Gemel

Levy

Simon

et al. 2014

Journal of Molecular and Cellular Cardiology

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Normal atrial conduction requires similar abundances and homogeneous/overlapping distributions of two connexins (Cx40 and Cx43). The remodeling of myocyte connections and altered electrical conduction associated with atrial fibrillation (AF) likely involves perturbations of these connexins. We conducted a comprehensive series of experiments to examine the abundances and distributions of Cx40 and Cx43 in the atria of AF patients. Atrial appendage tissues were obtained from patients with lone AF (paroxysmal or chronic) or normal controls. Connexins were localized by double label immunofluorescence confocal microscopy, and their overlap was quantified. Connexin proteins and mRNAs were quantified by immunoblotting and qRT-PCR. PCR amplified genomic DNA was sequenced to screen for connexin gene mutations or polymorphisms. Immunoblotting showed reductions of Cx40 protein (to 77% or 49% of control values in samples from patients with paroxysmal and chronic AF, respectively), but no significant changes of Cx43 protein levels in samples from AF patients. The extent of Cx43 immunostaining and its distribution relative to N-cadherin were preserved in the AF patient samples. Although there was variability of Cx40 staining among paroxysmal AF patients, all had some fields with substantial Cx40 heterogeneity and reduced overlap with Cx43. Cx40 immunostaining was severely reduced in all chronic AF patients. qRT-PCR showed no change in Cx43 mRNA levels, but reductions in total Cx40 mRNA (to <50%) and Cx40 transcripts A (to ~50%) and B (to <25%) as compared to controls. No Cx40 coding region mutations were identified. The frequency of promoter polymorphisms did not differ between AF patient samples and controls. Our data suggest that reduced Cx40 levels and heterogeneity of its distribution (relative to Cx43) are common in AF. Multiple mechanisms likely lead to reductions of functional Cx40 in atrial gap junctions and contribute to the pathogenesis of AF in different patients.

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“…that are crucial for cardiovascular development, including ANF and CX40 (27,(38)(39)(40)(41). In addition, loss-of-function mutations in several transcriptionally cooperative partners and target molecules of TBX5, including NKX2-5, GATA4, GATA5, GATA6, ANF and CX40, have been implicated in the pathogenesis of AF in humans (8)(9)(10)(11)(12)(13)(14)(42)(43)(44). Therefore, functionally impaired TBX5 may contribute to AF by reducing the expression of target genes.…”

Section: A B Cmentioning

confidence: 99%

TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome

Guo

Fang

et al. 2016

Molecular Medicine Reports

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Previous genome-wide association studies have demonstrated that single nucleotide polymorphisms in T‑box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt-Oram syndrome and paroxysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idiopathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild‑type counterpart using a dual‑luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co‑segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss‑of‑function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia.

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Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Cited by 33 publications

References 60 publications

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

Connexin40 abnormalities and atrial fibrillation in the human heart

TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome

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