Electrophysiological Study Of Long Q-T2Syndrome And Mutation Of HERG Gene

Congenital long-QT syndrome (LQTS) is a genetic disease characterized bydelayed cardiac repolarization and prolonged of the QT interval on theelectrocardiogram (ECG) and a variable clinical course with arrhythmia-relatedsyncope and sudden death. LQTS displays an autosomal dominant (Romano-Wardsyndrome) or recessive (Jervell Lange–Nielsen syndrome) inheritance pattern。We tryto examine the current changes of human HERG gene mutation derived from a LQT2Chinese family with a highly penetrating phenotype. The blood samples werecollected from8family members. The HERG gene mutations were identified usingstandard genetic tests. An A→G transition at1605(numbering from the initiationcodon of cDNA), resulting in replacement of the alanine at position535bymethionine (GTG→ATG, V535M), was identified in both the proband and his mother(II-2) by DNA sequencing. This mutation was localized to the S4voltage sensor ofthe HERG channel. Transient transfection of HERG channel cDNA (wild type orV535M plasmid pcDNA3.1) into the cultured cells. After transfection, membranecurrents were recorded using whole cell patch-clamp procedures. Compared to WT,V535M mutation significantly decreased tail currents of HERG. Gating kinetics ofHERG revealed that V1/2of steady-state inactivation shifted to negative potential inthe mutant. The time constant of recovery from inactivation was markedly prolongedin the mutant compared to WT among test potentials. V535M HERG mutationdemonstrates a markedly decreased tail current densities, which suggests that V535Mis a new loss of function mutation of HERG channel responsible for LQT2. The studyprovides a reliable basis for the diagnosis of clinical genetic arrhythmias and usefulideas for the study of such diseases.