Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation 2002 Jan 22;105(3):341-6
Date
01/24/2002Pubmed ID
11804990DOI
10.1161/hc0302.102592Scopus ID
2-s2.0-0037154288 (requires institutional sign-in at Scopus site) 182 CitationsAbstract
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.
Author List
Wang DW, Viswanathan PC, Balser JR, George AL Jr, Benson DWMESH terms used to index this publication - Major topics in bold
Action PotentialsAdult
Amino Acid Sequence
Atrioventricular Node
Cell Line
Child
Computer Simulation
Electrocardiography
Female
Heart Block
Humans
Kinetics
Male
Middle Aged
Molecular Sequence Data
Mutation
NAV1.5 Voltage-Gated Sodium Channel
Patch-Clamp Techniques
Protein Structure, Tertiary
Sequence Homology, Amino Acid
Sodium Channels