In order to assess the clinical manifestations and electrocardiogram (ECG) characteristics of Chinese long QT syndrome (LQTS) patients and describe the phenotype-genotype correlation, the subjects from 5 congenital LQTS families underwent clinical detailed examination including resting body surface ECG. QT interval and transmural dispersion of repolarization (TDR) were manually measured. Five families were genotyped by linkage analysis (polymerase chain reacting-short tandem repeat, PCR-STR). The phenotype-genotype correlation was analyzed. Four families were LQT2, 1 family was LQT3. Twenty-eight gene carriers were (14 males and 14 females) identified from 5 families. The mean QTc and TDRc were 0.56 +/- 0.04 s (range 0.42 to 0.63) and 0.16 +/- 0.04 s (range 0.09 to 0.24) respectively. 35.7% (10/28) had normal to borderline QTc (< or = 0.460 s). There was significant difference in QTc and TDRc between the patients with symptomatic LQTS and those with asymptomatic LQTS, and there was significant difference in TDRc between the asymptomatic patients and normal people also. A history of cardiac events was present in 50% (14/28), including 9 with syncope, 2 with sudden death (SD) and occurred in the absence of beta-blocker. Three SDs occurred prior to the diagnosis of LQTS and had no ECG record. Two out of 5 SDs (40%) occurred as the first symptom. Typical LQT2 T wave pattern were found in 40% (6/15) of all affected members. The appearing-normal T wave was found in one LQT3 family. Low penetrance of QTc and symptoms resulted in diagnostic challenge. ECG patterns and repolarization parameters may be used to predict the genotype in most families. Genetic test is very important for identification of gene carriers.
Arrhythmia/etiology ; Arrhythmia/genetics ; Asian Continental Ancestry Group ; Electrocardiography ; Genotype ; Long QT Syndrome/complications ; Long QT Syndrome/congenital ; Long QT Syndrome/*genetics ; Pedigree ; *Phenotype

Adult ; Asian Continental Ancestry Group ; genetics ; Female ; Humans ; Long QT Syndrome ; genetics ; Mutation, Missense ; Pedigree

Humans ; Mutation, Missense ; KCNQ1 Potassium Channel/genetics* ; Long QT Syndrome/genetics* ; Phenotype ; Mutation ; Pedigree

Humans ; Mutation, Missense ; KCNQ1 Potassium Channel/genetics* ; Long QT Syndrome/genetics* ; Phenotype ; Mutation ; Pedigree

Humans ; Diagnosis, Differential ; Long QT Syndrome/genetics* ; Syncope/diagnosis* ; Epilepsy/diagnosis* ; Electrocardiography

The human ether-a-go-go related gene (HERG) encodes the α -subunit of the rapid component of the delayed rectifier K(+) channel, which is essential for the third repolarization of the action potential of human myocardial cells. Mutations of the HERG gene can cause type II hereditary long QT syndrome (LQT2), characterized by prolongation of the QT interval, abnormal T wave, torsade de pointes, syncope and sudden cardiac death. So far more than 300 HERG mutations have been identified, the majority of which can cause LQT2 due to HERG protein trafficking defect. It has been reported that certain drugs can induce acquired long QT syndrome through directly blocking the pore and/or affecting the HERG trafficking. The trafficking defects and K(+) currents can be restored with low temperature and certain drugs. However, the mechanisms underlying defective trafficking caused by HERG mutations and the inhibition/restoration of HERG trafficking by drugs are still unknown. This review summarizes the current understanding of the molecular mechanisms including HERG trafficking under physiological and pathological conditions, and the effects of drugs on the HERG trafficking, in order to provide theoretical evidence for the diagnosis and treatment of long QT syndrome.
Animals ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; metabolism ; Humans ; Long QT Syndrome ; genetics ; metabolism ; physiopathology ; Protein Transport

OBJECTIVEJervell and Lange-Nielsen syndrome (JLNS) is a severe cardioauditory syndrome manifested as QT interval prolongation, abnormal T waves, and relative bradycardia ventricular tachyarrhythmias. In this report, we screened a nonconsanguineous families with JLNS for mutations in KCNQ1.

METHODSMutation analysis was performed by using purified PCR products to direct sequence analysis on an ABI-3730XL automated DNA sequencer. The whole sequence of proband' KCNQ1 was screened firstly, then screened the mutation exon sequences of others of the family and 50 unrelated normal persons.

RESULTSA heterogeneous mutation was identified in the patients of the JLNS family, a missense mutation (G-->T) at nucleotide 917 encoded in exon 6 of KCNQ1. This substitution leads to a change from glycine to Valine at codon 306(G306V) corresponding to the S5 transmembrane segment of KCNQ1. The other normal members of the family and 50 unrelated normal persons were not identified this mutation.

CONCLUSIONThe result suggested that not only homozygous mutations or compound heterozygous mutations in KCNQ1 could cause Jervell-Lange-Nielsen syndrome, the single heterozygous mutation may also cause Jervell-Lange-Nielsen syndrome.

Adolescent ; Adult ; Aged ; Child ; Female ; Genotype ; Humans ; Jervell-Lange Nielsen Syndrome ; genetics ; KCNQ1 Potassium Channel ; genetics ; Long QT Syndrome ; genetics ; Male ; Middle Aged ; Mutation, Missense ; Pedigree ; Young Adult

OBJECTIVETo investigate the functional expression of HERG mutation A561V detected in a Chinese congenital long QT syndrome family.

METHODSThe mutation gene A561V was cloned into eukaryotic expressive vector pcDNA3 by quick site-directed mutagenesis PCR and restriction enzymes. The wild-type HERG, heterozygous type HERG and HERG mutation A561V were respectively cotransfected with pRK5-GFP into HEK293 cells by Suprefact transfection regent. The protein expression was measured by immunofluorescence method and Western blot. The electrophysiological characteristics of transfected cells were determined by whole cell patch-clamp technique.

RESULTSDirect sequence analyses revealed a C to T transition at position 1682. A561V mutation was correctly combined to eukaryotic expressive vector pcDNA3 and expressed in HEK293 cells. The protein expression of mutation and heterozygosis were located in cytoplasm and cellular membrane. 155 kDa and 135 kDa protein bands were detected in wild type HERG channel while only 135 kDa protein band was shown in heterozygous and mutational channels. Significant HERG tail-current was recorded in wild type HERG channel but not in mutation and heterozygosis channels.

CONCLUSIONThis study evidenced a functional dominant-negative current suppression in HEK293 cells transfected with HERG mutation A561V.

Cell Line ; DNA Mutational Analysis ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; Gene Expression ; Humans ; Long QT Syndrome ; congenital ; genetics ; Mutation ; Patch-Clamp Techniques ; Transfection

OBJECTIVETo identify the electrophysiological properties of long-QT syndrome (LQTS) associated missense mutations in the outer mouth of the HERG potassium channel in vitro.

METHODSMutations V630A and N633S were constructed by Megaprimer PCR method and cRNA were produced by T7 RNA polymerase. The electrophysiological properties of the mutation were investigated in the Xenopus oocyte heterologous expression system.

RESULTSCoexpression of mutant and wild-type HERG subunits caused a dominant-negative effect, and the currents were significantly decreased. Compared with wild-type HERG channels, V630A and N633S mutations were related to decreased time constants for inactivation for V630A/WT and N633S/WT at all potentials, reduced slope conductance and the voltage dependence of steady-state inactivation was shifted to negative potentials for V630A/WT and N633S/WT.

CONCLUSIONPresent study shows that LQTS associated missense mutations located in the outer mouth of HERG cause a dominant-negative effect and alterations in steady-state voltage dependence of channel gating of heteromultimeric channels suggesting a reduction in expressional current might be one of the pathophysiologic mechanisms of LQTS.

Animals ; DNA Mutational Analysis ; ERG1 Potassium Channel ; Electrocardiography ; Ether-A-Go-Go Potassium Channels ; genetics ; Humans ; Long QT Syndrome ; genetics ; Mutation, Missense ; Oocytes ; Patch-Clamp Techniques ; RNA, Complementary ; Xenopus

In order to assess the clinical manifestations and electrocardiogram (ECG) characteristics of Chinese long QT syndrome (LQTS) patients and describe the phenotype-genotype correlation, the subjects from 5 congenital LQTS families underwent clinical detailed examination including resting body surface ECG. QT interval and transmural dispersion of repolarization (TDR) were manually measured. Five families were genotyped by linkage analysis (polymerase chain reacting-short tandem repeat, PCR-STR). The phenotype-genotype correlation was analyzed. Four families were LQT2, 1 family was LQT3. Twenty-eight gene carriers were (14 males and 14 females) identified from 5 families. The mean QTc and TDRc were 0.56 +/- 0.04 s (range 0.42 to 0.63) and 0.16 +/- 0.04 s (range 0.09 to 0.24) respectively. 35.7% (10/28) had normal to borderline QTc (< or = 0.460 s). There was significant difference in QTc and TDRc between the patients with symptomatic LQTS and those with asymptomatic LQTS, and there was significant difference in TDRc between the asymptomatic patients and normal people also. A history of cardiac events was present in 50% (14/28), including 9 with syncope, 2 with sudden death (SD) and occurred in the absence of beta-blocker. Three SDs occurred prior to the diagnosis of LQTS and had no ECG record. Two out of 5 SDs (40%) occurred as the first symptom. Typical LQT2 T wave pattern were found in 40% (6/15) of all affected members. The appearing-normal T wave was found in one LQT3 family. Low penetrance of QTc and symptoms resulted in diagnostic challenge. ECG patterns and repolarization parameters may be used to predict the genotype in most families. Genetic test is very important for identification of gene carriers.
Arrhythmias, Cardiac ; etiology ; genetics ; Asian Continental Ancestry Group ; Electrocardiography ; Female ; Genotype ; Humans ; Long QT Syndrome ; complications ; congenital ; genetics ; Male ; Pedigree ; Phenotype