© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia
aDepartment of Pediatrics, College of Medicine, National Taiwan University, National Taiwan University Hospital, No. 7, Chung-Shen South Road, Taipei, 100 Taiwan
bLaval Hospital, Research Centre, Sainte-Foy, Quebec, Canada, G1V 4G5, and Department of Medicine, Laval University, Quebec City, Quebec, Canada G1K 7P4
cDepartment of Internal Medicine, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
dDepartment of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital Taipei, Taiwan
eDepartment of Pediatrics, Ming-Shen General Hospital, Taoyuan, Taiwan
* Corresponding author. Fax: +886 2 23412601. Email address: mhwu{at}ha.mc.ntu.edu.tw
Objective: Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth.
Methods: Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia.
Results: A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Nav1.5 cardiac sodium channel, with a G
A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation.
Conclusions: These findings suggest that the Nav1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.
KEYWORDS Congenital long QT syndrome; Fetus; Newborn; Atrioventricular block; SCN5A; Nav1.5; Sodium channels
Time for primary review 17 days
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