Functional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant

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dc.authorid0000-0002-8647-6055
dc.authorid0000-0001-9008-4997
dc.authorid0000-0002-7199-583X
dc.contributor.authorŞahoğlu Göktaş, Sevilay
dc.contributor.authorKazcı, Yusuf Enes
dc.contributor.authorTuncay, Erkan
dc.contributor.authorTorun, Tuğçe
dc.contributor.authorAkdeniz, Celal
dc.contributor.authorTuzcu, Volkan
dc.contributor.authorÇağavi, Esra
dc.date.accessioned2022-11-22T11:16:23Z
dc.date.available2022-11-22T11:16:23Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Sağlık Bilimleri Enstitüsü, Sinirbilim Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Sağlık Bilimleri Enstitüsü, Tıbbi Biyoloji ve Genetik Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Çocuk Sağlığı ve Hastalıkları Ana Bilim Dalı
dc.description.abstractTachycardia is characterized by high beating rates that can lead to life-threatening fibrillations. Mutations in several ion-channel genes were implicated with tachycardia; however, the complex genetic contributors and their modes of action are still unclear. Here, we investigated the influence of an SCN5A gene variant on tachycardia phenotype by deriving patient-specific iPSCs and cardiomyocytes (iPSC-CM). Two tachycardia patients were genetically analyzed and revealed to inherit a heterozygous p.F1465L variant in the SCN5A gene. Gene expression and immunocytochemical analysis in iPSC-CMs generated from patients did not show any significant changes in mRNA levels of SCN5A or gross NaV1.5 cellular mislocalization, compared to healthy-derived iPSC-CMs. Electrophysiological and contraction imaging analysis in patient iPSC-CMs revealed intermittent fibrillation-like states, occasional arrhythmic events, and sustained high-paced contractions that could be selectively reduced by flecainide treatment. The patch-clamp analysis demonstrated a negative shift in the voltage-dependent activation at the patient-derived iPSC-CMs compared to the healthy control line, suggestive of a gain-of-function activity associated with the SCN5A(+/p.F1465L) variant. Our patient-derived iPSC-CM model recapitulated the clinically relevant characteristics of tachycardia associated with a novel pathogenic SCN5A(+/p.F1465L) variant leading to altered Na+ channel kinetics as the likely mechanism underlying high excitability and tachycardia phenotype.
dc.identifier.citationŞahoğlu Göktaş, S., Kazcı, Y. E., Tuncay, E., Torun, T., Akdeniz, C., Tuzcu, V. ... Çağavi, E. (2022). Functional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant. Journal of Cellular Physiology, 237(10), 3900-3911. https://doi.org/10.1002/jcp.30843
dc.identifier.doi10.1002/jcp.30843
dc.identifier.endpage3911
dc.identifier.issn0021-9541
dc.identifier.issn1097-4652
dc.identifier.issue10
dc.identifier.pmid35959596
dc.identifier.scopus2-s2.0-85135855979
dc.identifier.scopusqualityQ1
dc.identifier.startpage3900
dc.identifier.urihttps://doi.org/10.1002/jcp.30843
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10009
dc.identifier.volume237
dc.identifier.wos000839564000001en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorŞahoğlu Göktaş, Sevilay
dc.institutionauthorKazcı, Yusuf Enes
dc.institutionauthorTorun, Tuğçe
dc.institutionauthorAkdeniz, Celal
dc.institutionauthorTuzcu, Volkan
dc.institutionauthorÇağavi, Esra
dc.language.isoen
dc.publisherWiley
dc.relation.ispartofJournal of Cellular Physiologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.relation.tubitakinfo:eu-repo/grantAgreement/TUBITAK/SOBAG/213S192
dc.rightsinfo:eu-repo/semantics/embargoedAccess
dc.subjectCardiovascular Diseases
dc.subjectIn Vitro Disease Model
dc.subjectIPSC
dc.subjectSCN5A Variant
dc.subjectTachycardia
dc.titleFunctional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant
dc.typeArticle

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