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Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2021 Jul 27; Vol. 117 (9), pp. 2092-2107. - Publication Year :
- 2021
-
Abstract
- Aims: Several 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.<br />Methods and Results: Using 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.<br />Conclusion: Altogether, 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.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Arrhythmias, Cardiac metabolism
Arrhythmias, Cardiac physiopathology
Bone Diseases metabolism
Bone Diseases physiopathology
Cells, Cultured
Connexins genetics
Connexins metabolism
GATA4 Transcription Factor genetics
GATA4 Transcription Factor metabolism
Heart Rate
Homeodomain Proteins metabolism
Humans
Hypertelorism metabolism
Hypertelorism physiopathology
Intellectual Disability metabolism
Intellectual Disability physiopathology
Male
Mice, Inbred C57BL
Myopia metabolism
Myopia physiopathology
NAV1.5 Voltage-Gated Sodium Channel genetics
NAV1.5 Voltage-Gated Sodium Channel metabolism
Transcription Factors metabolism
Transcriptome
Gap Junction alpha-5 Protein
Mice
Action Potentials
Arrhythmias, Cardiac genetics
Bone Diseases genetics
Heart Ventricles metabolism
Homeodomain Proteins genetics
Hypertelorism genetics
Induced Pluripotent Stem Cells metabolism
Intellectual Disability genetics
Loss of Function Mutation
Myocytes, Cardiac metabolism
Myopia genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 117
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 32898233
- Full Text :
- https://doi.org/10.1093/cvr/cvaa259