Novel connexin40 missense mutations in patients with familial atrial fibrillation

Yang, Yi‐Qing; Liu, Xu; Zhang, Xian-Ling; Wang, Xinhua; Tan, H.S.; Shi, Haifeng; Jiang, Weifeng; Fang, Wei-Yi

doi:10.1093/europace/euq274

Cited by 65 publications

(51 citation statements)

References 46 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%

“…The referential genomic DNA sequence of GJA5 was derived from GenBank (accession number: NG_009369). With the aid of on-line Primer3 software (http://frodo.wi.mit.edu), the primer pairs used to amplify the complete coding region and splice junctions of GJA5 by polymerase chain reaction (PCR) were designed as previously described (54,55). PCR was performed using HotStar Taq DNA Polymerase (Qiagen, Hilden, Germany) on a Veriti ® Thermal Cycler (Applied Biosystems, Foster, CA, USA) with standard conditions and concentrations of reagents.…”

Section: Methodsmentioning

confidence: 99%

“…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). These findings provide a rationale to scan GJA5 as a logical candidate gene for AF.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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: Methodsmentioning

confidence: 99%

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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“…Various GJA5 defects other than p.Pro265Ser were previously associated with familial and sporadic atrial fibrillation. [21][22][23] Similarly, different mutations of cardiac transcription factor NKX2.5 have been identified in kindreds with conduction abnormalities (atrioventricular block) and concurrent congenital heart malformations, primarily secundum atrial septal defect, as well as in patients with sporadic TOF. 4,15,29 In the present study, variant p.Pro265Ser was found in B1% of TOF patients.…”

Section: Discussionmentioning

confidence: 99%

“…20 In humans, abnormalities in the GJA5 gene have been associated with atrial fibrillation. [21][22][23] In the present study, we evaluated whether GJA5 mutations might be pathogenic in isolated TOF, by gene screening in a series of non-syndromic TOF patients.…”

Section: Introductionmentioning

confidence: 99%

A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot

et al. 2012

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GJA5 gene (MIM no. 121013), localized at 1q21.1, encodes for the cardiac gap junction protein connexin 40. In humans, copy number variants of chromosome 1q21.1 have been associated with variable phenotypes comprising congenital heart disease (CHD), including isolated TOF. In mice, the deletion of Gja5 can cause a variety of complex CHDs, in particular of the cardiac outflow tract, corresponding to TOF in many cases. In the present study, we screened for mutations in the GJA5 gene 178 unrelated probands with isolated TOF. A heterozygous nucleotide change (c.793C4T) in exon 2 of the gene leading to the p.Pro265Ser variant at the carboxyl-terminus of the protein was found in two unrelated sporadic patients, one with classic anatomy and one with pulmonary atresia. This GJA5 missense substitution was not observed in 1568 ethnically-matched control chromosomes. Immunofluorescent staining and confocal microscopy revealed that cells expressing the mutant protein form sparse or no visible gap-junction plaques in the region of cell-cell contact. Moreover, analysis of the transfer of the gap junction permanent tracer lucifer yellow showed that cells expressing the mutant protein have a reduced rate of dye transfer compared with wild-type cells. Finally, use of a zebrafish model revealed that microinjection of the GJA5-p.Pro265Ser mutant disrupts overall morphology of the heart tube in the 37% (22/60) of embryos, compared with the 6% (4/66) of the GJA5 wild-type-injected embryos. These findings implicate GJA5 gene as a novel susceptibility gene for TOF.

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Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review

Bourgois,

Bizaoui,

Colson

et al. 2023

American J of Med Genetics Pt A

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Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long‐term follow‐up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis.

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Novel connexin40 missense mutations in patients with familial atrial fibrillation

Abstract: The findings expand the spectrum of mutations in connexin40 linked to AF and provide new insight into the molecular aetiology involved in the pathogenesis of AF.

Cited by 65 publications

References 46 publications

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review

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