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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents



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ID: 744091.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Switch From Fetal to Adult SCN5A Isoform in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Unmasks the Cellular Phenotype of a Conduction Disease-Causing Mutation
Authors:Veerman, C. C.; Mengarelli, I.; Lodder, E. M.; Kosmidis, G.; Bellin, M.; Zhang, M.; Dittmann, S.; Guan, K.; Wilde, A. A. M.; Schulze-Bahr, E.; Greber, B.; Bezzina, C. R.; Verkerk, A. O.
Date of Publication (YYYY-MM-DD):2017-07-24
Title of Journal:J am Heart Assoc
Volume:6
Issue / Number:7
Review Status:Internal review
Audience:Not Specified
Abstract / Description:BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate features of ion channel mutations causing inherited rhythm disease. However, the lack of maturity of these cells is considered a significant limitation of the model. Prolonged culture of hiPSC-CMs promotes maturation of these cells. We studied the electrophysiological effects of the I230T mutation in the sodium channel gene SCN5A in hiPSC-CMs generated from a homozygous (I230Thomo) and a heterozygous (I230Thet) individual from a family with recessive cardiac conduction disease. Since the I230T mutation occurs in the developmentally regulated "adult" isoform of SCN5A, we investigated the relationship between the expression fraction of the adult SCN5A isoform and the electrophysiological phenotype at different time points in culture. METHODS AND RESULTS: After a culture period of 20 days, sodium current (INa) was mildly reduced in I230Thomo hiPSC-CMs compared with control hiPSC-CMs, while I230Thet hiPSC-CMs displayed no reduction in INa. This coincided with a relatively high expression fraction of the "fetal" SCN5A isoform compared with the adult isoform as measured by quantitative polymerase chain reaction. Following prolonged culture to 66 days, the fraction of adult SCN5A isoform increased; this was paralleled by a marked decrease in INa in I230Thomo hiPSC-CMs, in line with the severe clinical phenotype in homozygous patients. At this time in culture, I230Thet hiPSC-CMs displayed an intermediate loss of INa, compatible with a gene dosage effect. CONCLUSIONS: Prolonged culture of hiPSC-CMs leads to an increased expression fraction of the adult sodium channel isoform. This new aspect of electrophysiological immaturity should be taken into account in studies that focus on the effects of SCN5A mutations in hiPSC-CMs.
Free Keywords:arrhythmia (heart rhythm disorders); sodium channels; stem cell
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands. Human Pluripotent Stem Cell Laboratory, Max Planck Institute for Molecular Biomedicine, Munster, Germany. Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany. Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Munster, Munster, Germany. Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany. Department of Experimental and Clinical Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands c.r.bezzina@amc.uva.nl a.o.verkerk@amc.nl. Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
Identifiers:ISSN:2047-9980 (Electronic) 2047-9980 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28739862 [ID No:2]
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