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

dc.contributor.coauthorAl Sayed, Zeina R
dc.contributor.coauthorCanac, Robin
dc.contributor.coauthorCimarosti, Bastien
dc.contributor.coauthorBonnard, Carine
dc.contributor.coauthorGourraud, Jean-Baptiste
dc.contributor.coauthorHamamy, Hanan
dc.contributor.coauthorGirardeau, Aurore
dc.contributor.coauthorJouni, Mariam
dc.contributor.coauthorJacob, Nicolas
dc.contributor.coauthorGaignerie, Anne
dc.contributor.coauthorChariau, Caroline
dc.contributor.coauthorDavid, Laurent
dc.contributor.coauthorForest, Virginie
dc.contributor.coauthorMarionneau, Céline
dc.contributor.coauthorCharpentier, Flavien
dc.contributor.coauthorLoussouarn, Gildas
dc.contributor.coauthorLamirault, Guillaume
dc.contributor.coauthorZibara, Kazem
dc.contributor.coauthorLemarchand, Patricia
dc.contributor.coauthorGaborit, Nathalie
dc.contributor.kuauthorKayserili, Hülya
dc.contributor.kuauthorReversade, Bruno
dc.date.accessioned2024-11-09T11:40:09Z
dc.date.issued2020
dc.description.abstractAims: 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.
dc.description.fulltextYES
dc.description.indexedbyPubMed
dc.description.issue9
dc.description.openaccessYES
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuEU
dc.description.sponsorshipNational Research Agency
dc.description.sponsorshipEuropean Union (EU)
dc.description.sponsorshipHorizon 2020
dc.description.sponsorshipMarie Curie Actions International Incoming Fellowship FP7-PEOPLE-2012-IIF
dc.description.sponsorshipLa Fédération Française de Cardiologie
dc.description.sponsorshipFondation LefoulonDelalande
dc.description.sponsorshipEiffel Scholarship Programme of Excellence (Campus France), Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie
dc.description.versionAuthor's final manuscript
dc.description.volume117
dc.identifier.doi10.1093/cvr/cvaa259
dc.identifier.eissn1755-3245
dc.identifier.embargoNO
dc.identifier.filenameinventorynoIR02906
dc.identifier.issn0008-6363
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85112477172
dc.identifier.urihttps://doi.org/10.1093/cvr/cvaa259
dc.keywordsIRX5 mutations
dc.language.isoeng
dc.publisherOxford University Press (OUP)
dc.relation.grantnoHEART iPS ANR-15-CE14-0019-01
dc.relation.grantnoPIIF-GA-2012-331436
dc.relation.ispartofCardiovascular Research
dc.relation.urihttp://cdm21054.contentdm.oclc.org/cdm/ref/collection/IR/id/9553
dc.titleHuman model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorKayserili, Hülya
local.contributor.kuauthorReversade, Bruno

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