Connexin45 (GJC1) loss-of-function mutation contributes to familial atrial fibrillation and conduction disease

Li, Ruogu; Xu, Ying‐Jia; Ye, Willy G.; Li, Yanjie; Chen, Honghong; Qiu, Xing‐Biao; Yang, Yi‐Qing; Bai, Donglin

doi:10.1016/j.hrthm.2020.12.033

Cited by 23 publications

(25 citation statements)

References 33 publications

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“…[85], NOTCH2 [86], LRP1 [87], CLU (clusterin) [88], FCN1 [89], CDKN1A [90], SMAD3 [91], HLA-E [92], PTPRC (protein tyrosine phosphatase receptor type C) [93], MYH9 [94], JAK3 [95], IL6R [96], TIMP1 [97], DOCK8 [98], TNFRSF1B [99], ITGAL (integrin subunit alpha L) [100], CD47 [101], RARA (retinoic acid receptor alpha) [102], DGKD (diacylglycerol kinase delta) [103], PLEK (pleckstrin) [104], PREX1 [105], BSCL2 [106], PANX1 [107], IRF7 [108] [116] were revealed to be expressed in diabetes mellitus, but these genes might be novel targets for GDM. SIX1 [117], GREM1 [118], GHRHR (growth hormone releasing hormone receptor) [119], GPR37L1 [120], CYP2J2 [121], AQP4 [122], ROS1 [123], LBP (lipopolysaccharide binding protein) [124], SGCD (sarcoglycan delta) [133], PTHLH [134], FAP (fibroblast activation protein alpha) [135], THSD7A [136], SHROOM3 [137], ETV1 [138], CYP24A1 [139], SLIT2 [140], GJC1 [141], PPARGC1A [142], TRPM3 [143], IGF1 [144], TRPV6 [145], TLR3 [146], BMP7 [147], DSG2 [148], POSTN (periostin) [149], ENOX1 [150], KCNA7…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Vastrad¹,

Vastrad²

2021

Preprint

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Gestational diabetes mellitus (GDM) is a metabolic disorder during pregnancy. Numerous biomarkers have been identified that are linked with the occurrence and development of GDM. The aim of this investigation was to identify differentially expressed genes (DEGs) in GDM using a bioinformatics approach to elucidate their molecular pathogenesis. GDM associated expression profiling by high throughput sequencing dataset (GSE154377) was obtained from Gene Expression Omnibus (GEO) database including 28 normal pregnancy samples and 33 GDM samples. DEGs were identified using DESeq2. The gene ontology (GO) and REACTOME pathway enrichments of DEGs were performed by g:Profiler. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into modules using the PEWCC1 algorithm. MiRNA-hub gene regulatory network and TF-hub gene regulatory network were performed with the miRNet database and NetworkAnalyst database. Receiver Operating Characteristic (ROC) analyses was conducted to validate the hub genes. A total of 953 DEGs were identified, of which 478 DEGs were up regulated and 475 DEGs were down regulated. Furthermore, GO and REACTOME pathway enrichment analysis demonstrated that these DEGs were mainly enriched in multicellular organismal process, cell activation, formation of the cornified envelope and hemostasis. TRIM54, ELAVL2, PTN, KIT, BMPR1B, APP, SRC, ITGA4, RPA1 and ACTB were identified as key genes in the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network. TRIM54, ELAVL2, PTN, KIT, BMPR1B, APP, SRC, ITGA4, RPA1 and ACTB in GDM were validated using ROC analysis. This investigation provides further insights into the molecular pathogenesis of GDM, which might facilitate the diagnosis and treatment of GDM.

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Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Vastrad¹,

Vastrad²

2021

Preprint

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“…Novel connexin gene-disease pairs have recently been reported on connexins that had not been previously linked to any inherited disease. For example, two variants in GJC1 (Cx45) were recently found to associate with inherited atrial conduction defects in an autosomal dominant manner [61,62]. In addition, some connexin gene variants that have been linked to one disease could have a subset of variants linked to one or more related or unrelated inherited diseases.…”

Section: Limitations Of Our Analysis and Future Directionsmentioning

confidence: 99%

Differential Domain Distribution of gnomAD- and Disease-Linked Connexin Missense Variants

Bai

Wang

et al. 2021

IJMS

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Twenty-one human genes encode connexins, a family of homologous proteins making gap junction (GJ) channels, which mediate direct intercellular communication to synchronize tissue/organ activities. Genetic variants in more than half of the connexin genes are associated with dozens of different Mendelian inherited diseases. With rapid advances in DNA sequencing technology, more variants are being identified not only in families and individuals with diseases but also in people in the general population without any apparent linkage to Mendelian inherited diseases. Nevertheless, it remains challenging to classify the pathogenicity of a newly identified connexin variant. Here, we analyzed the disease- and Genome Aggregation Database (gnomAD, as a proxy of the general population)-linked variants in the coding region of the four disease-linked α connexin genes. We found that the most abundant and position-sensitive missense variants showed distinct domain distribution preference between disease- and gnomAD-linked variants. Plotting missense variants on topological and structural models revealed that disease-linked missense variants are highly enriched on the structurally stable/resolved domains, especially the pore-lining domains, while the gnomAD-linked missense variants are highly enriched in the structurally unstable/unresolved domains, especially the carboxyl terminus. In addition, disease-linked variants tend to be on highly conserved residues and those positions show evolutionary co-variation, while the gnomAD-linked missense variants are likely on less conserved residue positions and on positions without co-variation. Collectively, the revealed distribution patterns of disease- and gnomAD-linked missense variants further our understanding of the GJ structure–biological function relationship, which is valuable for classifying the pathogenicity of newly identified connexin variants.

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“…Functional analysis of the S140G-mutant KCNQ1 unveiled a gain-of-function impact on the currents of KCNQ1 /KCNE1 and KCNQ1 /KCNE2 channels, which significantly shorten the action potential duration of atrial myocytes thereby increasing the vulnerability to AF ( Chen et al , 2003 ). Up to now, in addition to the association of ~140 genetic loci with increased predisposition to AF revealed by genome-wide association studies ( Kim et al , 2021 ), rare variations in over 50 distinct genes have been discovered to contribute to AF, amidst which the majority encode cardiac potassium ion channels, sodium channels, gap junction channels, calcium channels, signaling molecules, structural proteins and transcription factors ( Choi et al , 2020 ; Ghazizadeh et al , 2020 ; Hansen et al , 2020 ; Huang et al , 2020 ; Jiang et al , 2020 ; Ragab et al , 2020 ; Roselli et al , 2020 ; van Ouwerkerk et al , 2020 ; Wu et al , 2020 ; Yang et al , 2020 ; Chalazan et al , 2021 ; Lazarte et al , 2021 ; Li et al , 2021a , b ; Ziki et al , 2021 ). Interestingly, multiple variations in or near the PRRX1 gene, has recently been associated with an enhanced susceptibility to AF in humans ( Tucker et al , 2017 ; Guo et al , 2021 ; Wu et al , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A novel PRRX1 loss-of-function variation contributing to familial atrial fibrillation and congenital patent ductus arteriosus

Zhang

Guo

et al. 2022

Genet. Mol. Biol.

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Atrial fibrillation (AF) represents the most common type of sustained cardiac arrhythmia in humans and confers a significantly increased risk for thromboembolic stroke, congestive heart failure and premature death. Aggregating evidence emphasizes the predominant genetic defects underpinning AF and an increasing number of deleterious variations in more than 50 genes have been involved in the pathogenesis of AF. Nevertheless, the genetic basis underlying AF remains incompletely understood. In the current research, by whole-exome sequencing and Sanger sequencing analysis in a family with autosomal-dominant AF and congenital patent ductus arteriosus (PDA), a novel heterozygous variation in the PRRX1 gene encoding a homeobox transcription factor critical for cardiovascular development, NM_022716.4:c.373G>T;p.(Glu125 * ), was identified to be in co-segregation with AF and PDA in the whole family. The truncating variation was not detected in 306 unrelated healthy individuals employed as controls. Quantitative biological measurements with a reporter gene analysis system revealed that the Glu125 * -mutant PRRX1 protein failed to transactivate its downstream target genes SHOX2 and ISL1 , two genes that have been causally linked to AF. Conclusively, the present study firstly links PRRX1 loss-of-function variation to AF and PDA, suggesting that AF and PDA share a common abnormal developmental basis in a proportion of cases.

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Connexin45 (GJC1) loss-of-function mutation contributes to familial atrial fibrillation and conduction disease

Cited by 23 publications

References 33 publications

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Differential Domain Distribution of gnomAD- and Disease-Linked Connexin Missense Variants

A novel PRRX1 loss-of-function variation contributing to familial atrial fibrillation and congenital patent ductus arteriosus

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