Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome. Pediatr Res 2003 May;53(5):744-8
Date
03/07/2003Pubmed ID
12621127DOI
10.1203/01.PDR.0000059750.17002.B6Scopus ID
2-s2.0-0242515866 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
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.
Author List
Johnson WH Jr, Yang P, Yang T, Lau YR, Mostella BA, Wolff DJ, Roden DM, Benson DWMESH terms used to index this publication - Major topics in bold
Base SequenceCation Transport Proteins
DNA-Binding Proteins
ERG1 Potassium Channel
Electrocardiography
Ether-A-Go-Go Potassium Channels
Family Health
Female
Homozygote
Humans
Infant, Newborn
Long QT Syndrome
Male
Membrane Potentials
Molecular Sequence Data
Pedigree
Phenotype
Potassium Channels
Potassium Channels, Voltage-Gated
Severity of Illness Index
Trans-Activators
Transcriptional Regulator ERG
