Back to Search Start Over

Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Authors :
Bastien Cimarosti
Guillaume Lamirault
Hanan Hamamy
Nathalie Gaborit
Céline Marionneau
Flavien Charpentier
Gildas Loussouarn
Laurent David
Kazem Zibara
Nicolas Jacob
Virginie Forest
Mariam Jouni
Caroline Chariau
Carine Bonnard
Hülya Kayserili
Bruno Reversade
Anne Gaignerie
Jean-Baptiste Gourraud
Robin Canac
Zeina R Al Sayed
Patricia Lemarchand
Aurore Girardeau
Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945)
Reversade, Bruno
Al Sayed, Zeina R
Canac, Robin
Cimarosti, Bastien
Bonnard, Carine
Gourraud, Jean-Baptiste
Hamamy, Hanan
Girardeau, Aurore
Jouni, Mariam
Jacob, Nicolas
Gaignerie, Anne
Chariau, Caroline
David, Laurent
Forest, Virginie
Marionneau, Céline
Charpentier, Flavien
Loussouarn, Gildas
Lamirault, Guillaume
Zibara, Kazem
Lemarchand, Patricia
Gaborit, Nathalie
School of Medicine
unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE)
Université de Nantes (UN)-Université de Nantes (UN)
Agency for science, technology and research [Singapore] (A*STAR)
Department of Genetic Medicine and Development [Geneva]
Université de Genève (UNIGE)
Koç University
Structure fédérative de recherche François Bonamy (SFR François Bonamy)
Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)
Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE)
Institut de transplantation urologie-néphrologie (ITUN)
Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)
National University of Singapore (NUS)
University of Amsterdam [Amsterdam] (UvA)
Laboratory of Stem Cells [Lebanese, Beirut] (ER045-PRASE)
Lebanese University [Beirut] (LU)
This work was funded by grants from The National Research Agency [HEART iPS ANR-15-CE14-0019-01], and La Fédération Française de Cardiologie. Nathalie Gaborit was laureate of fellowships from Fondation Lefoulon-Delalande and International Incoming Fellowship FP7-PEOPLE-2012-IIF [PIIF-GA-2012-331436]. Zeina R. Al Sayed is supported by Eiffel scholarship program of Excellence (Campus France), by Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie.
ACS - Heart failure & arrhythmias
ARD - Amsterdam Reproduction and Development
Unité de recherche de l'institut du thorax (ITX-lab)
Université de Genève = University of Geneva (UNIGE)
Source :
Cardiovascular Research, Cardiovascular Research, Oxford University Press (OUP), 2020, pp.cvaa259. ⟨10.1093/cvr/cvaa259⟩, Cardiovascular Research, Oxford University Press (OUP), 2021, 117 (9), pp.2092-2107. ⟨10.1093/cvr/cvaa259⟩, Cardiovascular research, 117(9), 2092-2107. Oxford University Press, Cardiovascular Research, 2021, 117 (9), pp.2092-2107. ⟨10.1093/cvr/cvaa259⟩
Publication Year :
2020
Publisher :
Oxford University Press (OUP), 2020.

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. 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. 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 />National Research Agency; European Union (EU); Horizon 2020; Marie Curie Actions International Incoming Fellowship FP7-PEOPLE-2012-IIF; La Fédération Française de Cardiologie; Fondation LefoulonDelalande; Eiffel Scholarship Programme of Excellence (Campus France), Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie

Details

Language :
English
ISSN :
00086363
Database :
OpenAIRE
Journal :
Cardiovascular Research, Cardiovascular Research, Oxford University Press (OUP), 2020, pp.cvaa259. ⟨10.1093/cvr/cvaa259⟩, Cardiovascular Research, Oxford University Press (OUP), 2021, 117 (9), pp.2092-2107. ⟨10.1093/cvr/cvaa259⟩, Cardiovascular research, 117(9), 2092-2107. Oxford University Press, Cardiovascular Research, 2021, 117 (9), pp.2092-2107. ⟨10.1093/cvr/cvaa259⟩
Accession number :
edsair.doi.dedup.....af5b851a531ee9f55381a590e7821912
Full Text :
https://doi.org/10.1093/cvr/cvaa259⟩