SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome
- 10 July 2007
- journal article
- case report
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 116 (2), 134-142
- https://doi.org/10.1161/circulationaha.106.659086
Abstract
Background— Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming α-subunit associated with 1 or more auxiliary β-subunits. Four different β-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. Methods and Results— We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Navβ-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel α-subunit (hNaV1.5). Compared with the wild-type, L179F-β4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-β4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. Conclusions— We provide the seminal report of SCN4B-encoded Navβ4 as a novel LQT3-susceptibility gene.This publication has 50 references indexed in Scilit:
- Time-Dependent Block and Resurgent Tail Currents Induced by Mouse β4154–167 Peptide in Cardiac Na+ ChannelsThe Journal of general physiology, 2006
- A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardiaCardiovascular Research, 2004
- Distinct Subcellular Localization of Different Sodium Channel α and β Subunits in Single Ventricular Myocytes From Mouse HeartCirculation, 2004
- A Novel mutation L619F in the cardiac Na channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gatingHuman Mutation, 2003
- The intracellular segment of the sodium channel β1 subunit is required for its efficient association with the channel α subunitJournal of Neurochemistry, 2001
- Sodium Channel β Subunits Mediate Homophilic Cell Adhesion and Recruit Ankyrin to Points of Cell-Cell ContactPublished by Elsevier BV ,2000
- Na+ channel subunits and Ig domainsNature, 1996
- Infants with long-QT syndrome and 2:1 atrioventricular blockAmerican Heart Journal, 1995
- Structure and function of the β2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motifCell, 1995
- The cloning and expression of a sodium channel β1-subunit cDNA from human brainHuman Molecular Genetics, 1993