Document Detail

Ion channel mechanisms related to sudden cardiac death in phenotype-negative long-QT syndrome genotype-phenotype correlations of the KCNQ1(S349W) mutation.
MedLine Citation:
PMID:  20662986     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype-negative long-QT syndrome (LQTS) are limited.
METHODS AND RESULTS: We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc-matched carriers of haploinsufficient missense (n = 30) and nonsense (n = 45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild-type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc-matched haploinsufficent missense (21%, P = 0.004) and nonsense (25%, P = 0.01) mutations.
CONCLUSIONS: The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal-range QTc.
Samuel Horr; Ilan Goldenberg; Arthur J Moss; Jin O-Uchi; Alon Barsheshet; Heather Connelly; Daniel A Gray; Wojciech Zareba; Coeli M B Lopes
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cardiovascular electrophysiology     Volume:  22     ISSN:  1540-8167     ISO Abbreviation:  J. Cardiovasc. Electrophysiol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-14     Completed Date:  2011-06-17     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  9010756     Medline TA:  J Cardiovasc Electrophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  193-200     Citation Subset:  IM    
Copyright Information:
© 2010 Wiley Periodicals, Inc.
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MeSH Terms
Death, Sudden, Cardiac*
Genetic Predisposition to Disease / genetics*
Ion Channel Gating / genetics*
KCNQ1 Potassium Channel / genetics*
Long QT Syndrome / genetics*
Polymorphism, Single Nucleotide
Grant Support
Reg. No./Substance:
0/KCNQ1 Potassium Channel; 0/KCNQ1 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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