title: Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome.
abstract: Previous studies have identified mutations in five ion channel genes as a cause of long QT syndrome, a heterogeneous disorder characterized by prolongation of the QT interval, multiform ventricular tachycardia (torsades de pointes), seizures, syncope, and sudden death. However, in these studies, the average age of initial symptoms is in the third decade of life or later, and few reports have described the genetic causes of long QT syndrome presenting in the prenatal or neonatal period. We used a candidate gene approach to identify the genetic cause of long QT syndrome in an infant whose initial manifestations were detected in utero. Direct bidirectional sequencing of long QT syndrome genes identified a previously unreported HERG missense mutation (R752Q). Three asymptomatic family members were heterozygous for R752Q, and the proband, who manifested ventricular tachycardia in utero, was homozygous. R752Q was not found in 100 normal unrelated chromosomes. Paternal DNA was unavailable for testing. Transient transfection of HERG generated robust IKr, but no current was observed for the mutant HERG. The HERG mutant, R752Q, is associated with a mild phenotype, inasmuch as family members with a heterozygous mutation appear unaffected. The homozygous mutation results in absence of functional IKr, causing a profound loss of HERG channel function, creating the equivalent of a "HERG knockout" and leading to a severe phenotype.
authors.affiliation: Department of Pediatrics, L.M. Bargeron Division of Pediatric Cardiology, University of Alabama at Birmingham, USA. wjohnson@uab.edu
authors.forename: Walter H
authors.initials: WH
authors.lastname: Johnson
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Yung R
authors.initials: YR
authors.lastname: Lau
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Mostella
authors.forename: Daynna J
authors.initials: DJ
authors.lastname: Wolff
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
mesh_terms: D001483:Base Sequence; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005192:Family Health; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D012720:Severity of Illness Index; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG