Document Detail

Cardiac sodium channel dysfunction in sudden infant death syndrome.
MedLine Citation:
PMID:  17210841     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Mutations in genes responsible for the congenital long-QT syndrome, especially SCN5A, have been identified in some cases of sudden infant death syndrome. In a large-scale collaborative genetic screen, several SCN5A variants were identified in a Norwegian sudden infant death syndrome cohort (n=201). We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts.
METHODS AND RESULTS: Whole-cell sodium currents were measured in tsA201 cells transiently transfected with recombinant wild-type or mutant SCN5A cDNA (hH1) coexpressed with the human beta1 subunit. All variants exhibited defects in the kinetics and voltage dependence of inactivation. Five variants (S216L, T1304M, F1486L, F2004L, and P2006A) exhibited significantly increased persistent sodium currents (range, 0.5% to 1.7% of peak current) typical of SCN5A mutations associated with long-QT syndrome. These same 5 variants also displayed significant depolarizing shifts in voltage dependence of inactivation (range, 5 to 14 mV) and faster recovery from inactivation, but F1486L uniquely exhibits a depolarizing shift in the conductance-voltage relationship. Three alleles (delAL586-587, R680H, and V1951L) exhibited increased persistent current only under conditions of internal acidosis (R680H) or when expressed in the context of a common splice variant (delQ1077), indicating that they have a latent dysfunctional phenotype.
CONCLUSIONS: Our present results greatly expand the spectrum of functionally characterized SCN5A variants associated with sudden infant death syndrome and provide further biophysical correlates of arrhythmia susceptibility in this syndrome.
Dao W Wang; Reshma R Desai; Lia Crotti; Marianne Arnestad; Roberto Insolia; Matteo Pedrazzini; Chiara Ferrandi; Ashild Vege; Torleiv Rognum; Peter J Schwartz; Alfred L George
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-01-08
Journal Detail:
Title:  Circulation     Volume:  115     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-23     Completed Date:  2007-02-14     Revised Date:  2011-07-22    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  368-76     Citation Subset:  AIM; IM    
Departments of Pharmacology, Vanderbilt University, Nashville, Tenn, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Arrhythmias, Cardiac / complications,  genetics,  physiopathology
Cohort Studies
DNA, Complementary / genetics
Gene Expression Regulation
Genetic Predisposition to Disease
Genetic Testing / methods
Genetic Variation / genetics
Long QT Syndrome / complications*,  genetics*,  physiopathology
Muscle Proteins / genetics*,  physiology*
Mutation, Missense / genetics*
Risk Factors
Sodium Channels / genetics*,  physiology*
Sudden Infant Death / etiology*,  genetics*
Grant Support
Reg. No./Substance:
0/DNA, Complementary; 0/Muscle Proteins; 0/Sodium Channels; 0/sodium channel protein type 5 subunit alpha
Comment In:
Circulation. 2007 Jul 24;116(4):e92; author reply e93   [PMID:  17646591 ]

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

Previous Document:  Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs s...
Next Document:  Accelerated mitochondrial adenosine diphosphate/adenosine triphosphate transport improves hypertensi...