| Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). | |
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MedLine Citation:
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PMID: 12163457 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1. In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death. To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome. |
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Authors:
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Martin Tristani-Firouzi; Judy L Jensen; Matthew R Donaldson; Valeria Sansone; Giovanni Meola; Angelika Hahn; Said Bendahhou; Hubert Kwiecinski; Anna Fidzianska; Nikki Plaster; Ying-Hui Fu; Louis J Ptacek; Rabi Tawil |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 110 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 2002 Aug |
Date Detail:
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Created Date: 2002-08-06 Completed Date: 2002-09-24 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 381-8 Citation Subset: AIM; IM |
Affiliation:
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Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah 84112, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult Animals Arrhythmias, Cardiac Child Electrophysiology Female Heart / physiopathology Heart Defects, Congenital Humans Long QT Syndrome / genetics*, physiopathology Male Middle Aged Mutation* Paralyses, Familial Periodic / genetics*, physiopathology Potassium Channels, Inwardly Rectifying / genetics*, physiology Rabbits Syndrome |
| Grant Support | |
ID/Acronym/Agency:
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HL-38616/HL/NHLBI NIH HHS; M01-RR-00044/RR/NCRR NIH HHS; RR-00064/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Potassium Channels, Inwardly Rectifying |
| Comments/Corrections | |
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