Title: Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia.

Authors: Lisa L Murphy, Anita J Moon-Grady, Bettina F Cuneo, Ronald T Wakai, Suhong Yu, Jennifer D Kunic, D Woodrow Benson, Alfred L George

Journal, date & volume: Heart Rhythm, 2012 Apr , 9, 590-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22064211

Abstract
Congenital long-QT syndrome (LQTS) may present during fetal development and can be life-threatening. The molecular mechanism for the unusual early onset of LQTS during fetal development is unknown.We sought to elucidate the molecular basis for severe fetal LQTS presenting at 19 weeks' gestation, the earliest known presentation of this disease.Fetal magnetocardiography was used to demonstrated torsades de pointes and a prolonged rate-corrected QT interval. In vitro electrophysiological studies were performed to determine functional consequences of a novel SCN5A mutation found in the fetus.The fetus presented with episodes of ventricular ectopy progressing to incessant ventricular tachycardia and hydrops fetalis. Genetic analysis disclosed a novel, de novo heterozygous mutation (L409P) and a homozygous common variant (R558 in SCN5A). In vitro electrophysiological studies demonstrated that the mutation in combination with R558 caused significant depolarized shifts in the voltage dependence of inactivation and activation, faster recovery from inactivation, and a 7-fold higher level of persistent current. When the mutation was engineered in a fetal-expressed SCN5A splice isoform, channel dysfunction was markedly potentiated. Also, R558 alone in the fetal splice isoform evoked a large persistent current, and hence both alleles were dysfunctional.We report the earliest confirmed diagnosis of symptomatic LQTS and present evidence that mutant cardiac sodium channel dysfunction is potentiated by a developmentally regulated alternative splicing event in SCN5A. Our findings provide a plausible mechanism for the unusual severity and early onset of cardiac arrhythmia in fetal LQTS.