Multiple arrhythmic syndromes in a newborn, owing to a novel mutation in SCN5A

TY - JOUR

T1 - Multiple arrhythmic syndromes in a newborn, owing to a novel mutation in SCN5A

AU - Calloe, Kirstine

AU - Schmitt, Nicole

AU - Grubb, Søren

AU - Pfeiffer, Ryan

AU - David, Jens-Peter

AU - Kanter, Ronald

AU - Cordeiro, Jonathan M

AU - Antzelevitch, Charles

AU - Callø, Kirstine

PY - 2011/10

Y1 - 2011/10

N2 - Background. Mutations in the SCN5A gene have been linked to Brugada syndrome (BrS), conduction disease, Long QT syndrome (LQT3), atrial fibrillation (AF), and to pre- and neonatal ventricular arrhythmias. Objective. The objective of this study is to characterize a novel mutation in Na v1.5 found in a newborn with fetal chaotic atrial tachycardia, postpartum intraventricular conduction delay, and QT interval prolongation. Methods. Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced, revealing a novel missense mutation (Q270K) in SCN5A. Na v1.5 wild type (WT) and Q270K were expressed in CHO-K1 with and without the Na vβ1 subunit. Results. Patch-clamp analysis showed ~40% reduction in peak sodium channel current (I Na) density for Q270K compared with WT. Fast and slow decay of I Na were significantly slower in Q270K. Steady-state activation and inactivation of Q270K channels were shifted to positive potentials, and window current was increased. The tetrodotoxin-sensitive late I Na was increased almost 3- fold compared with WT channels. Ranolazine reduced late I Na in WT and Q270K channels, while exerting minimal effects on peak I Na. Conclusion. The Q270K mutation in SCN5A reduces peak I Na while augmenting late I Na, and may thus underlie the development of atrial tachycardia, intraventricular conduction delay, and QT interval prolongation in an infant.

AB - Background. Mutations in the SCN5A gene have been linked to Brugada syndrome (BrS), conduction disease, Long QT syndrome (LQT3), atrial fibrillation (AF), and to pre- and neonatal ventricular arrhythmias. Objective. The objective of this study is to characterize a novel mutation in Na v1.5 found in a newborn with fetal chaotic atrial tachycardia, postpartum intraventricular conduction delay, and QT interval prolongation. Methods. Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced, revealing a novel missense mutation (Q270K) in SCN5A. Na v1.5 wild type (WT) and Q270K were expressed in CHO-K1 with and without the Na vβ1 subunit. Results. Patch-clamp analysis showed ~40% reduction in peak sodium channel current (I Na) density for Q270K compared with WT. Fast and slow decay of I Na were significantly slower in Q270K. Steady-state activation and inactivation of Q270K channels were shifted to positive potentials, and window current was increased. The tetrodotoxin-sensitive late I Na was increased almost 3- fold compared with WT channels. Ranolazine reduced late I Na in WT and Q270K channels, while exerting minimal effects on peak I Na. Conclusion. The Q270K mutation in SCN5A reduces peak I Na while augmenting late I Na, and may thus underlie the development of atrial tachycardia, intraventricular conduction delay, and QT interval prolongation in an infant.

KW - Animals

KW - Arrhythmias, Cardiac

KW - CHO Cells

KW - Cell Line, Transformed

KW - Cricetinae

KW - DNA Mutational Analysis

KW - Female

KW - Humans

KW - Infant, Newborn

KW - Ion Channels

KW - Membrane Potentials

KW - Mutation, Missense

KW - NAV1.5 Voltage-Gated Sodium Channel

KW - Patch-Clamp Techniques

KW - Sodium Channels

KW - Syndrome

U2 - 10.1139/y11-070

DO - 10.1139/y11-070

M3 - Journal article

C2 - 21895525

SN - 0008-4212

VL - 89

SP - 723

EP - 736

JO - Canadian Journal of Physiology and Pharmacology

JF - Canadian Journal of Physiology and Pharmacology

IS - 10

ER -