Reduced connexin40 protein expression in the right atrial appendage of patients bearing the minor connexin40 allele (−44 G → A)

Chaldoupi, Sevasti‐Maria; Hubens, Lisette E. G.; Duijzentkunst, Daan A. Smit; Stuijvenberg, Leonie van; Bierhuizen, Marti F.A.; Aarnhem, Egidius E.H.L. van; Nelen, Marcel; Bakker, Jacques M.T. de; Hauer, Richard N.W.; Rijen, Harold V.M. van; Loh, Peter; Veen, Toon A.B. van

doi:10.1093/europace/eus047

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…Multiple GJA5 mutations or polymorphisms have been previously involved in AF (48)(49)(50)(51)(52)(53)(54)(55). Similar to the present findings, Yang et al (54,55) have previously performed a sequence analysis of the GJA5 gene in a total of 344 index patients with lone AF, and identified four novel heterozygous missense mutations (p.Q49X, p.V85I, p.L221I and p.L229M), with a mutational prevalence of ~1.16%.…”

Section: Discussionsupporting

confidence: 86%

“…However, functional changes in GJA5 alone may not be sufficient for significantly prolonged P-wave duration, PQ interval, QRS duration and QT duration in the surface electrocardiogram, as observed in these AF families and other AF patients (48)(49)(50)(51)(52)(53)(54)(55). Additionally, full deficiency for GJA5 has been associated with altered electrocardiographic parameters in GJA5 knockout mice, in contrast to haploinsufficiency for GJA5 (57).…”

Section: Discussionmentioning

confidence: 92%

“…In human, cardiac GJA5 remodeling may lead to abnormal electrical coupling, forming an electrophysiological matrix with potential arrhythmogenic effect (47). By reducing GJA5 protein levels, several closely linked polymorphisms in the promoter region of the GJA5 gene have been strongly associated with enhanced atrial vulnerability and increased risk for lone AF (48)(49)(50)(51)(52). Furthermore, multiple somatic and germline mutations in GJA5 have been reported to underlie AF (53)(54)(55).…”

Section: Introductionmentioning

confidence: 99%

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Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Shi

Yang

Wang

et al. 2012

Molecular Medicine Reports

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Abstract. Atrial fibrillation (AF) is the most common form of cardiac arrhythmia observed in clinical practice and a major contributor to cardiovascular morbidity and mortality. Accumulating evidence indicates a substantial genetic basis for AF. However, AF is genetically heterogeneous and the hereditary components responsible for AF remain to be identified in the majority of patients. The cardiac gap junction protein α 5 (GJA5) is specifically expressed in atrial myocytes and is associated with the coordinated electrical activation of the atria, providing a rationale to screen GJA5 as a logical candidate gene for AF. A cohort of 310 unrelated patients with lone AF and their available relatives were included in this study. A group of 200 unrelated healthy individuals matched for age, gender and race were also included as controls. The entire coding region and splice sites of the GJA5 gene were initially sequenced in 310 unrelated AF patients. The relatives of mutation carriers and 200 controls were subsequently genotyped for the presence of identified mutations. As a result, 4 novel heterozygous GJA5 mutations, p.K107R, p.L223M, p.Q236H and p.I257L, were identified in 4 of 310 unrelated AF patients, respectively, with a prevalence of ~1.29%. Genetic analysis of the carriers' families showed that in each family the missense mutation was present in all the affected family members. Absent in the 400 reference alleles, these mutations altered the amino acids highly conserved among various species, with the exception of p.I257L. In conclusion, this study expands the spectrum of GJA5 mutations associated with AF and provides novel insights into the molecular basis of AF, suggesting potential implications for the improved, gene-specific rhythm control strategies.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Shi

Yang

Wang

et al. 2012

Molecular Medicine Reports

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“…The Cx40 promoters contain polymorphic variants that have been linked to AF (and other disease states including hypertension) in some studies [17–21]. We used PCR to amplify the regions flanking exons 1A and 1B (from all control and AF patient samples) and directly sequenced the DNA products to identify these polymorphisms (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Prior studies have linked AF to polymorphic variants (SNPs) of each of the Cx40 promoters [17, 19, 39]. These SNPs can cause decreased transcription of the corresponding transcripts and/or reduced Cx40 levels [19, 21]. The prior studies disagree about which SNP is linked to AF, perhaps due to the analysis of different populations.…”

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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Association between polymorphisms in connexin 40 gene (Cx40) and risk of atrial fibrillation: a meta-analysis based on 3,452 subjects

Zheng

Liu

et al. 2023

Biomarkers

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Reduced connexin40 protein expression in the right atrial appendage of patients bearing the minor connexin40 allele (−44 G → A)

Cited by 5 publications

References 40 publications

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Connexin40 abnormalities and atrial fibrillation in the human heart

Association between polymorphisms in connexin 40 gene (Cx40) and risk of atrial fibrillation: a meta-analysis based on 3,452 subjects

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