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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2002-1-23
pubmed:abstractText
BACKGROUND: Three distinct cardiac arrhythmia disorders, the long-QT syndrome, Brugada syndrome, and conduction system disease, have been associated with heterozygous mutations in the cardiac voltage-gated sodium channel alpha-subunit gene (SCN5A). We present clinical, genetic, and biophysical features of 2 new SCN5A mutations that result in atrioventricular (AV) conduction block. Methods and Results- SCN5A was used as a candidate gene in 2 children with AV block. Molecular genetic studies revealed G to A transition mutations that resulted in the substitution of serine for glycine (G298S) in the domain I S5-S6 loop and asparagine for aspartic acid (D1595N) within the S3 segment of domain IV. The functional consequences of G298S and D1595N were assessed by whole-cell patch clamp recording of recombinant mutant channels coexpressed with the beta1 subunit in a cultured cell line (tsA201). Both mutations impair fast inactivation but do not exhibit sustained non-inactivating currents. The mutations also reduce sodium current density and enhance slower inactivation components. Action potential simulations predict that this combination of biophysical abnormalities will significantly slow myocardial conduction velocity. CONCLUSIONS: A distinct pattern of biophysical abnormalities not previously observed for any other SCN5A mutant have been recognized in association with AV block. These data provide insight into the distinct clinical phenotypes resulting from mutation of a single ion channel.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1524-4539
pubmed:author
pubmed:issnType
Electronic
pubmed:day
22
pubmed:volume
105
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
341-6
pubmed:dateRevised
2011-7-22
pubmed:meshHeading
pubmed-meshheading:11804990-Action Potentials, pubmed-meshheading:11804990-Adult, pubmed-meshheading:11804990-Amino Acid Sequence, pubmed-meshheading:11804990-Atrioventricular Node, pubmed-meshheading:11804990-Cell Line, pubmed-meshheading:11804990-Child, pubmed-meshheading:11804990-Computer Simulation, pubmed-meshheading:11804990-Electrocardiography, pubmed-meshheading:11804990-Female, pubmed-meshheading:11804990-Heart Block, pubmed-meshheading:11804990-Humans, pubmed-meshheading:11804990-Kinetics, pubmed-meshheading:11804990-Male, pubmed-meshheading:11804990-Middle Aged, pubmed-meshheading:11804990-Molecular Sequence Data, pubmed-meshheading:11804990-Mutation, pubmed-meshheading:11804990-Patch-Clamp Techniques, pubmed-meshheading:11804990-Protein Structure, Tertiary, pubmed-meshheading:11804990-Sequence Homology, Amino Acid, pubmed-meshheading:11804990-Sodium Channels
pubmed:year
2002
pubmed:articleTitle
Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block.
pubmed:affiliation
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn, and Department of Pediatrics, Medical University of South Carolina, Charleston, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't