Rebs, Sabine

[["dc.bibliographiccitation.firstpage","9"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","21"],["dc.bibliographiccitation.volume","113"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Fomin, Andrey"],["dc.contributor.author","Luo, Xiaojing"],["dc.contributor.author","Li, Wener"],["dc.contributor.author","Fischer, Claudia"],["dc.contributor.author","Özcelik, Cemil"],["dc.contributor.author","Perrot, Andreas"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Haas, Jan"],["dc.contributor.author","Vidal, Ramon Oliveira"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Khadjeh, Sara"],["dc.contributor.author","Meder, Benjamin"],["dc.contributor.author","Bonn, Stefan"],["dc.contributor.author","Linke, Wolfgang A."],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Guan, Kaomei"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.date.accessioned","2018-04-23T11:49:17Z"],["dc.date.available","2018-04-23T11:49:17Z"],["dc.date.issued","2017"],["dc.description.abstract","The ability to generate patient-specific induced pluripotent stem cells (iPSCs) provides a unique opportunity for modeling heart disease in vitro. In this study, we generated iPSCs from a patient with dilated cardiomyopathy (DCM) caused by a missense mutation S635A in RNA-binding motif protein 20 (RBM20) and investigated the functionality and cell biology of cardiomyocytes (CMs) derived from patient-specific iPSCs (RBM20-iPSCs). The RBM20-iPSC-CMs showed abnormal distribution of sarcomeric α-actinin and defective calcium handling compared to control-iPSC-CMs, suggesting disorganized myofilament structure and altered calcium machinery in CMs of the RBM20 patient. Engineered heart muscles (EHMs) from RBM20-iPSC-CMs showed that not only active force generation was impaired in RBM20-EHMs but also passive stress of the tissue was decreased, suggesting a higher visco-elasticity of RBM20-EHMs. Furthermore, we observed a reduced titin (TTN) N2B-isoform expression in RBM20-iPSC-CMs by demonstrating a reduction of exon skipping in the PEVK region of TTN and an inhibition of TTN isoform switch. In contrast, in control-iPSC-CMs both TTN isoforms N2B and N2BA were expressed, indicating that the TTN isoform switch occurs already during early cardiogenesis. Using next generation RNA sequencing, we mapped transcriptome and splicing target profiles of RBM20-iPSC-CMs and identified different cardiac gene networks in response to the analyzed RBM20 mutation in cardiac-specific processes. These findings shed the first light on molecular mechanisms of RBM20-dependent pathological cardiac remodeling leading to DCM. Our data demonstrate that iPSC-CMs coupled with EHMs provide a powerful tool for evaluating disease-relevant functional defects and for a deeper mechanistic understanding of alternative splicing-related cardiac diseases."],["dc.identifier.doi","10.1016/j.yjmcc.2017.09.008"],["dc.identifier.gro","3142517"],["dc.identifier.pmid","28941705"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16493"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13672"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/191"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A08: Translationale und posttranslationale Kontrolle trunkierter Titinproteine in Kardiomyozyten von Patienten mit dilatativer Kardiomyopathie"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","0022-2828"],["dc.relation.workinggroup","RG Guan (Application of patient-specific induced pluripotent stem cells in disease modelling)"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Linke (Kardiovaskuläre Physiologie)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","13"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","117"],["dc.contributor.author","Haupt, Luis Peter"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Maurer, Wiebke"],["dc.contributor.author","Hübscher, Daniela"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Maus, Andreas"],["dc.contributor.author","Köhne, Steffen"],["dc.contributor.author","Tappu, Rewati"],["dc.contributor.author","Haas, Jan"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2022-04-01T10:01:09Z"],["dc.date.available","2022-04-01T10:01:09Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20 + B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca 2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca 2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients."],["dc.identifier.doi","10.1007/s00395-022-00918-7"],["dc.identifier.pii","918"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/105613"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation.eissn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S2666166721008236"],["dc.bibliographiccitation.firstpage","101117"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","STAR Protocols"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Buchwald, Tjark Alexander"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2022-04-01T10:02:33Z"],["dc.date.available","2022-04-01T10:02:33Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1016/j.xpro.2021.101117"],["dc.identifier.pii","S2666166721008236"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/105942"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation.issn","2666-1667"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","A quantitative RT-PCR protocol to adapt and quantify RBM20-dependent exon splicing of targets at the human locus"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","101746"],["dc.bibliographiccitation.journal","Stem Cell Research"],["dc.bibliographiccitation.volume","44"],["dc.contributor.author","Hübscher, Daniela"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Maurer, Wiebke"],["dc.contributor.author","Ghadri, Jelena R."],["dc.contributor.author","Dressel, Ralf"],["dc.contributor.author","Templin, Christian"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2020-12-10T15:21:15Z"],["dc.date.available","2020-12-10T15:21:15Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1016/j.scr.2020.101746"],["dc.identifier.issn","1873-5061"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/72964"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Generation of iPSC-lines from two independent Takotsubo syndrome patients with recurrent Takotsubo events"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","136"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","147"],["dc.bibliographiccitation.volume","164"],["dc.contributor.author","Emanuelli, Giulia"],["dc.contributor.author","Zoccarato, Anna"],["dc.contributor.author","Reumiller, Christina M."],["dc.contributor.author","Papadopoulos, Angelos"],["dc.contributor.author","Chong, Mei"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Betteridge, Kai"],["dc.contributor.author","Beretta, Matteo"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Shah, Ajay M."],["dc.date.accessioned","2022-06-01T09:39:03Z"],["dc.date.available","2022-06-01T09:39:03Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1016/j.yjmcc.2021.12.001"],["dc.identifier.pii","S0022282821002285"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108375"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-572"],["dc.relation.issn","0022-2828"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","A roadmap for the characterization of energy metabolism in human cardiomyocytes derived from induced pluripotent stem cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","101901"],["dc.bibliographiccitation.journal","Stem Cell Research"],["dc.bibliographiccitation.volume","47"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Sedaghat-Hamedani, Farbod"],["dc.contributor.author","Kayvanpour, Elham"],["dc.contributor.author","Meder, Benjamin"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2021-04-14T08:24:33Z"],["dc.date.available","2021-04-14T08:24:33Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1016/j.scr.2020.101901"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81329"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.issn","1873-5061"],["dc.title","Generation of pluripotent stem cell lines and CRISPR/Cas9 modified isogenic controls from a patient with dilated cardiomyopathy harboring a RBM20 p.R634W mutation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","102263"],["dc.bibliographiccitation.journal","Stem Cell Research"],["dc.bibliographiccitation.volume","53"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Beier, Jakob"],["dc.contributor.author","Argyriou, Loukas"],["dc.contributor.author","Schill, Tillmann"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Vollmann, Dirk"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2021-06-01T10:49:55Z"],["dc.date.available","2021-06-01T10:49:55Z"],["dc.date.issued","2021"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.1016/j.scr.2021.102263"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/86461"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation.issn","1873-5061"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","Generation and cardiac differentiation of an induced pluripotent stem cell line from a patient with arrhythmia-induced cardiomyopathy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Stem Cells International"],["dc.bibliographiccitation.lastpage","11"],["dc.bibliographiccitation.volume","2019"],["dc.contributor.author","Hübscher, Daniela"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Haupt, Luis"],["dc.contributor.author","Borchert, Thomas"],["dc.contributor.author","Guessoum, Celina Isabell"],["dc.contributor.author","Treu, Franziska"],["dc.contributor.author","Köhne, Steffen"],["dc.contributor.author","Maus, Andreas"],["dc.contributor.author","Hambrecht, Mario"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Dressel, Ralf"],["dc.contributor.author","Uy, Angela"],["dc.contributor.author","Jakob, Mark"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2020-12-10T18:37:41Z"],["dc.date.available","2020-12-10T18:37:41Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1155/2019/2181437"],["dc.identifier.pmid","31467559"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16503"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77068"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/330"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","A High-Throughput Method as a Diagnostic Tool for HIV Detection in Patient-Specific Induced Pluripotent Stem Cells Generated by Different Reprogramming Methods"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","12990"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","22"],["dc.contributor.affiliation","Sedaghat-Hamedani, Farbod; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.affiliation","Rebs, Sabine; 3Clinic for Cardiology and Pneumology, Georg-August-University Göttingen, 37073 Göttingen, Germany; sabine.rebs@med.uni-goettingen.de (S.R.); katrin.streckfuss@med.uni-goettingen.de (K.S.-B.)"],["dc.contributor.affiliation","El-Battrawy, Ibrahim; 2DZHK (German Centre for Cardiovascular Research), Heidelberg-Mannheim, 17475 Greifswald, Germany; ibrahim.elbattrawy2006@gmail.com (I.E.-B.); xiaobo.zhou@medma.uni-heidelberg.de (X.Z.); Ibrahim.Akin@medma.uni-heidelberg.de (I.A.)"],["dc.contributor.affiliation","Chasan, Safak; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.affiliation","Krause, Tobias; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.affiliation","Haas, Jan; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.affiliation","Zhong, Rujia; 6Department of Medicine, University Medical Centre Mannheim (UMM), 68159 Mannheim, Germany; Rujia.Zhong@medma.uni-heidelberg.de (R.Z.); Zhenxing.Liao@medma.uni-heidelberg.de (Z.L.); Qiang.Xu@medma.uni-heidelberg.de (Q.X.)"],["dc.contributor.affiliation","Liao, Zhenxing; 6Department of Medicine, University Medical Centre Mannheim (UMM), 68159 Mannheim, Germany; Rujia.Zhong@medma.uni-heidelberg.de (R.Z.); Zhenxing.Liao@medma.uni-heidelberg.de (Z.L.); Qiang.Xu@medma.uni-heidelberg.de (Q.X.)"],["dc.contributor.affiliation","Xu, Qiang; 6Department of Medicine, University Medical Centre Mannheim (UMM), 68159 Mannheim, Germany; Rujia.Zhong@medma.uni-heidelberg.de (R.Z.); Zhenxing.Liao@medma.uni-heidelberg.de (Z.L.); Qiang.Xu@medma.uni-heidelberg.de (Q.X.)"],["dc.contributor.affiliation","Zhou, Xiaobo; 2DZHK (German Centre for Cardiovascular Research), Heidelberg-Mannheim, 17475 Greifswald, Germany; ibrahim.elbattrawy2006@gmail.com (I.E.-B.); xiaobo.zhou@medma.uni-heidelberg.de (X.Z.); Ibrahim.Akin@medma.uni-heidelberg.de (I.A.)"],["dc.contributor.affiliation","Akin, Ibrahim; 2DZHK (German Centre for Cardiovascular Research), Heidelberg-Mannheim, 17475 Greifswald, Germany; ibrahim.elbattrawy2006@gmail.com (I.E.-B.); xiaobo.zhou@medma.uni-heidelberg.de (X.Z.); Ibrahim.Akin@medma.uni-heidelberg.de (I.A.)"],["dc.contributor.affiliation","Zitron, Edgar; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.affiliation","Frey, Norbert; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.affiliation","Streckfuss-Bömeke, Katrin; 3Clinic for Cardiology and Pneumology, Georg-August-University Göttingen, 37073 Göttingen, Germany; sabine.rebs@med.uni-goettingen.de (S.R.); katrin.streckfuss@med.uni-goettingen.de (K.S.-B.)"],["dc.contributor.affiliation","Kayvanpour, Elham; 1Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, 69120 Heidelberg, Germany; Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de (F.S.-H.); Safak.Chasan@med.uni-heidelberg.de (S.C.); ttkrause@me.com (T.K.); jan.haas@med.uni-heidelberg.de (J.H.); edgar.zitron@med.uni-heidelberg.de (E.Z.); Norbert.Frey@med.uni-heidelberg.de (N.F.)"],["dc.contributor.author","Sedaghat-Hamedani, Farbod"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","El-Battrawy, Ibrahim"],["dc.contributor.author","Chasan, Safak"],["dc.contributor.author","Krause, Tobias"],["dc.contributor.author","Haas, Jan"],["dc.contributor.author","Zhong, Rujia"],["dc.contributor.author","Liao, Zhenxing"],["dc.contributor.author","Xu, Qiang"],["dc.contributor.author","Zhou, Xiaobo"],["dc.contributor.author","Kayvanpour, Elham"],["dc.contributor.author","Akin, Ibrahim"],["dc.contributor.author","Zitron, Edgar"],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2022-02-01T10:31:49Z"],["dc.date.available","2022-02-01T10:31:49Z"],["dc.date.issued","2021"],["dc.date.updated","2022-09-03T23:21:13Z"],["dc.description.abstract","Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype."],["dc.description.abstract","Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype."],["dc.identifier.doi","10.3390/ijms222312990"],["dc.identifier.pii","ijms222312990"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/98952"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-517"],["dc.relation.eissn","1422-0067"],["dc.rights","CC BY 4.0"],["dc.title","Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]