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Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction
- 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
- Subjects :
- conduction
IRX5 mutations
Physiology
Transcription factor complex
Connexin
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
030204 cardiovascular system & hematology
Biology
arrhythmia
Ventricular action potential
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
transcription factors
Cardiac conduction
Transcription factor
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
030304 developmental biology
0303 health sciences
GATA4
Sodium channel
Depolarization
Human-induced pluripotent stem cells
Cell biology
human induced pluripotent stem cells
cardiovascular system
IRX5
Cardiology and Cardiovascular Medicine
Hamamy syndrome
Subjects
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⟩