ArticleCardiovascular research2021
Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction.
Article in Cardiovascular research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 24 citations in OpenAlex.
- Selective activation of tetrodotoxin-sensitive sodium channels by AaH-II drives arrhythmogenic late Na+ current in the heart.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
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- Multifaceted role of Iroquois signaling in development and diseases.Molecules and cells · 2025Review
- Connexin 40 in atrial fibrillation: pathophysiological roles and regulatory mechanisms.Annals of medicine · 2025Review
- TheiScience · 2025Article
- IRX5 Promoted SREBP1-Mediated de Novo Fatty Acid Synthesis via HMGN4 in Hepatocellular Carcinoma.Journal of cellular and molecular medicine · 2025Article
- Rod-shaped micropatterning enhances the electrophysiological maturation of cardiomyocytes derived from human induced pluripotent stem cells.Stem cell reports · 2024Article
- Subepicardial Cardiomyopathy: A Disease Underlying J-Wave Syndromes and Idiopathic Ventricular Fibrillation.Circulation · 2023Article
- Technologies, strategies, and cautions when deconvoluting genome-wide association signals: FTO in focus.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2023Review
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- Microevolutionary mechanism of high-altitude adaptation in Tibetan chicken populations from an elevation gradient.Evolutionary applications · 2022Article
- Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.Nature communications · 2022Article
- Searching for genetic modulators of the phenotypic heterogeneity in Brugada syndrome.PloS one · 2022Article
- Clinical and Molecular Update on the Fourth Reported Family with Hamamy Syndrome.Molecular syndromology · 2021Article
- Understanding the role of Iroquois homeobox transcription factor 5 (IRX5) in cardiac function: getting to the (human) heart of the matter.Cardiovascular research · 2021Article
- A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype.Clinical and translational medicine · 2021Article
- Epigenetic Changes GoverningInternational journal of molecular sciences · 2021Article
- Role of Non-Coding Variants in Brugada Syndrome.International journal of molecular sciences · 2020Review
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22 authors at 5 institutions in 6 countries.
Funding
Abstract
aimsSeveral inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. METHODS AND
resultsUsing human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression.
conclusionAltogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases.
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