| Patient-specific induced pluripotent stem-cell models for long-QT syndrome. | |
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MedLine Citation:
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PMID: 20660394 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier I(Ks) current. METHODS: We screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene. We obtained dermal fibroblasts from two family members and two healthy controls and infected them with retroviral vectors encoding the human transcription factors OCT3/4, SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific protocol, these cells were then directed to differentiate into cardiac myocytes. RESULTS: Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Individual cells showed a “ventricular,” “atrial,” or “nodal” phenotype, as evidenced by the expression of cell-type–specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in “ventricular” and “atrial” cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects. Further characterization of the role of the R190Q–KCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, we showed that myocytes derived from patients with long-QT syndrome type 1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype. CONCLUSIONS: We generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological features of the disorder. (Funded by the European Research Council and others.) |
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Authors:
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Alessandra Moretti; Milena Bellin; Andrea Welling; Christian Billy Jung; Jason T Lam; Lorenz Bott-Flügel; Tatjana Dorn; Alexander Goedel; Christian Höhnke; Franz Hofmann; Melchior Seyfarth; Daniel Sinnecker; Albert Schömig; Karl-Ludwig Laugwitz |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-21 |
Journal Detail:
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Title: The New England journal of medicine Volume: 363 ISSN: 1533-4406 ISO Abbreviation: N. Engl. J. Med. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-07 Completed Date: 2010-10-14 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 0255562 Medline TA: N Engl J Med Country: United States |
Other Details:
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Languages: eng Pagination: 1397-409 Citation Subset: AIM; IM |
Affiliation:
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Cardiology Division, First Department of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Action Potentials* Adrenergic beta-Antagonists / pharmacology, therapeutic use Adult Aged Cardiotonic Agents / pharmacology Child Female Fibroblasts / cytology Gene Expression Humans Induced Pluripotent Stem Cells / physiology* Isoproterenol / pharmacology KCNQ1 Potassium Channel / genetics* Male Mutation, Missense Myocytes, Cardiac / cytology*, drug effects, physiology Pedigree Phenotype Potassium Channel Blockers / pharmacology Potassium Channels / physiology Reverse Transcriptase Polymerase Chain Reaction Romano-Ward Syndrome / drug therapy, genetics, physiopathology* |
| Chemical | |
Reg. No./Substance:
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0/Adrenergic beta-Antagonists; 0/Cardiotonic Agents; 0/KCNQ1 Potassium Channel; 0/KCNQ1 protein, human; 0/Potassium Channel Blockers; 0/Potassium Channels; 7683-59-2/Isoproterenol |
| Comments/Corrections | |
Comment In:
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N Engl J Med. 2010 Oct 7;363(15):1471-2
[PMID:
20925550
]
Arch Iran Med. 2010 Nov;13(6):573-5 [PMID: 21039019 ] N Engl J Med. 2011 Jan 13;364(2):181; author reply 181-2 [PMID: 21226590 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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