Document Detail

Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel.
MedLine Citation:
PMID:  9495298     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: A heritable form of the long-QT syndrome (LQT3) has been linked to mutations in the cardiac sodium channel gene (SCN5A). Recently, a sporadic SCN5A mutation was identified in a Japanese girl afflicted with the long-QT syndrome. In contrast to the heritable mutations, this externally positioned domain IV, S4 mutation (R1623Q) neutralized a charged residue that is critically involved in activation-inactivation coupling.
METHODS AND RESULTS: We have characterized the R1623Q mutation in the human cardiac sodium channel (hH1) using both whole-cell and single-channel recordings. In contrast to the autosomal dominant LQT3 mutations, R1623Q increased the probability of long openings and caused early reopenings, producing a threefold prolongation of sodium current decay. Lidocaine restored rapid decay of the R1623Q macroscopic current.
CONCLUSIONS: The R1623Q mutation produces inactivation gating defects that differ mechanistically from those caused by LQT3 mutations. These findings provide a biophysical explanation for this severe long-QT phenotype and extend our understanding of the mechanistic role of the S4 segment in cardiac sodium channel inactivation gating and class I antiarrhythmic drug action.
N G Kambouris; H B Nuss; D C Johns; G F Tomaselli; E Marban; J R Balser
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  97     ISSN:  0009-7322     ISO Abbreviation:  Circulation     Publication Date:  1998 Feb 
Date Detail:
Created Date:  1998-03-17     Completed Date:  1998-03-17     Revised Date:  2011-07-22    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  640-4     Citation Subset:  AIM; IM    
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md 21287, USA.
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MeSH Terms
Anti-Arrhythmia Agents / pharmacology
CHO Cells
Genes, Dominant
Lidocaine / pharmacology
Long QT Syndrome / genetics*,  metabolism
Mutagenesis, Site-Directed
Oocytes / drug effects
Patch-Clamp Techniques
Point Mutation*
Recombinant Fusion Proteins / metabolism
Sodium Channels / drug effects,  genetics*,  metabolism
Grant Support
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Recombinant Fusion Proteins; 0/Sodium Channels; 0/sodium channel protein type 5 subunit alpha; 137-58-6/Lidocaine

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