ISL1 loss-of-function variation causes familial atrial fibrillation

Wu, Shaohui; Wang, Xinghua; Xu, Ying‐Jia; Gu, Jun; Yang, Chenxi; Qiao, Qi; Guo, Xiaofeng; Guo, Yu-Han; Qiu, Xing‐Biao; Jiang, Weifeng; Yang, Yi‐Qing

doi:10.1016/j.ejmg.2020.104029

Cited by 13 publications

(16 citation statements)

References 58 publications

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“…The truncating variation was neither detected in 612 referential chromosomes nor retrieved in the Single Nucleotide Polymorphism database , the Single Nucleotide Polymorphism database , the Human Gene Mutation Database , the 1000 Genomes Project database or the UK Biobank database . Functional research unveiled that Glu125 * -mutant PRRX1 lost transcriptional activation on the promoters of SHOX2 and ISL1 , two genes where variations have been discovered to result in AF and CHD ( Blaschke et al , 2007 ; Hoffmann et al , 2016 , 2019 ; Li et al , 2018 ; Ma et al , 2019 ; Wang et al , 2019 ; Wu et al , 2020 ). These findings indicate that genetically defective PRRX1 contributes to AF and PDA in this family.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Whole-exome sequencing (WES) was performed as previously described. 50,51) Briefly, each exome library was constructed using 3 μg of genomic DNA and captured using the SureSelect XT Human All Exon V6 Kit (Agilent Technologies, Santa Clara, CA, USA) according to the manufacturer's protocol. The constructed exome libraries were enriched and sequenced on the Illumina HiSeq 2000 Genome Analyzer (Illumina, San Diego, CA, USA) using the HiSeq Sequencing Kit (Illumina) according to the manufacturer's analysis of the WES data was conducted as described elsewhere.…”

Section: Study Subjectsmentioning

confidence: 99%

“…The constructed exome libraries were enriched and sequenced on the Illumina HiSeq 2000 Genome Analyzer (Illumina, San Diego, CA, USA) using the HiSeq Sequencing Kit (Illumina) according to the manufacturer's analysis of the WES data was conducted as described elsewhere. 50,51) The minor allele frequency for each genetic variant was calculated according to such population genetic databases as the NHLBI Exome Sequencing Project database (https://ev s.gs.washington.edu/EVS/), the Single Nucleotide Polymorphism database (https://www.ncbi.nlm.nih.gov/snp/), and the Genome Aggregation Database (https://gnomad.br oadinstitute.org/). The disease-causing potential of a novel genetic variation was predicted using PolyPhen-2 (http://g enetics.bwh.harvard.edu/pph2), MutationTaster (http://ww w.mutationtaster.org), SIFT (http://sift.jcvi.org/www/SIFT_ enst_submit.html), and PROVEAN (http://provean.jcvi.org/ index.php).…”

Section: Study Subjectsmentioning

confidence: 99%

“…54,55) Cell transfection and dual-luciferase assay: COS-7 and 293T cells were cultivated and transiently transfected with various plasmids using the Lipofectamine 3000 reagent (Invitrogen) as described previously. 50,51) The pGL4.75 plasmid (Promega), which expresses the Renilla luciferase, was used as an internal control to normalize the transfection efficiency. In brief, COS-7 cells were transfected with 400 ng of empty pcDNA3.1, 400 ng of wild-type SOX17-pcDNA3.1, 400 ng of Gln127*-mutant SOX-pcDNA3.1, 200 ng of wild-type SOX-pcDNA3.1 plus 200 ng of empty pcDNA3.1, or 200 ng of wild-type SOX17-pcDNA 3.1 plus 200 ng of Gln127*-mutant SOX-pcDNA3.1, together with 1000 ng of NOTCH1-luc and 25 ng of pGL 4.75.…”

Section: Study Subjectsmentioning

confidence: 99%

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SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension

Wang

et al. 2021

Int. Heart J.

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Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM _022454.4: c.379C>T; p.(Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode β-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

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Identification and functional analysis of genetic variants of ISL1 gene promoter in human atrial septal defects

Yin

Chen

et al. 2022

The Journal of Gene Medicine

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Background: Atrial septal defect (ASD) is a common type of congenital heart disease.A gene promoter plays pivotal role in the disease development. This study was designed to investigate the pathological role of variants of the ISL1 gene promoter region in ASD patients.Methods: Total DNA extracted from 625 subjects, including 332 ASD patients and 293 healthy controls, was sequenced to identify variants in the promoter region of ISL1 gene. Further functional analyses of the variants were performed with dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). All possible binding sites of transcription factor affected by the identified variants were predicted using the JASPAR database.Results: Four variants in the ISL1 gene promoter were found only in patients with ASD by sequencing. Three of the four variants [g.4923 G > C (rs541081886), g.5079 A > G (rs1371835943) and g.5309 G > A (rs116222082)] significantly decreased the transcriptional activities compared with the wild-type ISL1 gene promoter (p < 0.05).The EMSA revealed that these variants [g.4923 G > C (rs541081886), g.5079 A > G (rs1371835943) and g.5309 G > A (rs116222082)] in the ISL1 gene promoter affected the number and affinity of binding sites of transcription factors. Further analysis with the online JASPAR database demonstrated that a cluster of putative binding sites for transcription factors may be altered by these variants.Conclusions: These sequence variants identified from the promoter region of ISL1 gene in ASD patients are probably involved in the development of ASD by affecting the transcriptional activity and altering ISL1 levels. Therefore, these findings may provide new insights into the molecular etiology and potential therapeutic strategy of ASD.

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ISL1 loss-of-function variation causes familial atrial fibrillation

Cited by 13 publications

References 58 publications

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

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

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension

Identification and functional analysis of genetic variants of ISL1 gene promoter in human atrial septal defects

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