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

OBJECTIVETo construct the pcDNA3-HERG-G572R expression vector and establish a cell line stably expressing HKE-HERG-G572R.

METHODSHERG-G572R mutant fragment was constructed by over-lap extension PCR and validated by DNA sequencing. The HKE-HERG-G572R expression vector was constructed and transfected into HEK293 cells to obtain a cell line stably expressing HKE-HERG-G572R.

RESULTSThe pcDNA3-HERG-G572R expression vector was successfully constructed and the cell line stably expressing HKE-HERG-G572R was established. Real-time PCR and Western blotting revealed a 632-fold HKE-HERG-G572R overexpression in the transfected HEK293 cells as compared with that in control HEK293 cells transfected with pcDNA3 (P<0.01).

CONCLUSIONThe protocol can be used to construct the cell line stably expressing HKE-HERG-G572R to provide a cell model for studying individualized therapy.

Base Sequence ; Ether-A-Go-Go Potassium Channels ; genetics ; Gene Expression ; Genetic Vectors ; HEK293 Cells ; metabolism ; Humans ; Mutation ; Transfection

BACKGROUNDCongenital long QT syndrome (LQTS) is an ion channelopathy associated with genetic mutations. It is well known that most LQTS patients (91%) have a single mutation. The purpose of this study was to investigate the clinical characteristics of congenital LQTS patients with bigenic mutations in Taiwan, China.

METHODSCongenital LQTS patients were recruited consecutively at Taiwan University Hospital in Taiwan from 2003 to 2009. The diagnosis of LQTS was defined by an LQTS Schwartz score greater than 4. Mutation screening in KCNQ1, KCNH2, KCNE1, and SCN5A was performed using direct sequencing.

RESULTSThree of 16 LQTS patients (18.7%) were identified with bigenic mutations. One patient had missense mutations in KCNQ1 and KCNH2, the second in KCNQ1 and KCNE1, and the third in KCNH2 and SCN5A. The mean age at onset of LQTS for patients with bigenic mutations was (17 ± 3) years, and all of these patients were female. Two of them experienced seizure and one presented with syncope, although one of them had a family history of syncope. The mean QTc interval was (515 ± 17) ms, similar to those with single mutation or SNPs ((536 ± 74) ms, P = 0.63). Compared to those LQTS patients with single mutation or SNPs, a significantly higher percentage of LQTS patients with bigenic mutations presented with seizure and were younger at onset of the first index event (P = 0.03 and 0.001, respectively), but lower percentage of them presented with sudden cardiac death (P = 0.03).

CONCLUSIONSAlthough the percentage of bigenic mutations in LQTS is less than 10% in Caucasian populations, we identified 3 of 16 LQTS patients (18.7%, 95% confidence interval: 0.04-0.46) with bigenic mutations in Taiwan. However, the severity of their clinical presentations was not higher than those patients with single mutation or SNPs.

Adolescent ; Adult ; Aged ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; Female ; Genotype ; Humans ; KCNQ1 Potassium Channel ; genetics ; Long QT Syndrome ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; NAV1.5 Voltage-Gated Sodium Channel ; genetics ; Polymorphism, Single Nucleotide ; genetics ; Potassium Channels, Voltage-Gated ; genetics ; Young Adult

Mutation or common intronic variants in cardiac ion channel genes have been suggested to be associated with sudden cardiac death caused by idiopathic ventricular tachyarrhythmia. This study aimed to find mutations in cardiac ion channel genes of Korean sudden cardiac arrest patients with structurally normal heart and to verify association between common genetic variation in cardiac ion channel and sudden cardiac arrest by idiopathic ventricular tachyarrhythmia in Koreans. Study participants were Korean survivors of sudden cardiac arrest caused by idiopathic ventricular tachycardia or fibrillation. All coding exons of the SCN5A, KCNQ1, and KCNH2 genes were analyzed by Sanger sequencing. Fifteen survivors of sudden cardiac arrest were included. Three male patients had mutations in SCN5A gene and none in KCNQ1 and KCNH2 genes. Intronic variant (rs2283222) in KCNQ1 gene showed significant association with sudden cardiac arrest (OR 4.05). Four male sudden cardiac arrest survivors had intronic variant (rs11720524) in SCN5A gene. None of female survivors of sudden cardiac arrest had SCN5A gene mutations despite similar frequencies of intronic variants between males and females in 55 normal controls. Common intronic variant in KCNQ1 gene is associated with sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia in Koreans.
Adolescent ; Adult ; Aged ; Arrhythmias, Cardiac/genetics ; *Death, Sudden, Cardiac ; Ether-A-Go-Go Potassium Channels/genetics ; Female ; Genetic Markers ; Genetic Predisposition to Disease ; Genetic Variation ; Heart/physiology ; Heart Conduction System/abnormalities ; Humans ; KCNQ1 Potassium Channel/*genetics ; Male ; Middle Aged ; NAV1.5 Voltage-Gated Sodium Channel/*genetics ; Republic of Korea ; Tachycardia, Ventricular/*genetics ; Ventricular Fibrillation/*genetics ; Young Adult

OBJECTIVETo investigate the expression of the Eag1 K( +) channel in the prostate cancer (PCa) tissue, its correlation with the development and progression of PCa, and whether it could be a target for the diagnosis and treatment of PCa.

METHODSWe used RT-PCR and immunohistochemistry to determine the mRNA and protein expressions of the Eag1 K(+) channel in the normal peritumoral tissue of androgen-dependent PCa (ADPCa) (group A) and androgen-independent PCa (AIPCa) (group B) as well as in the tumorous tissue of ADPCa (group C) and AIPCa (group D).

RESULTSThe relative coefficients of the mRNA expression of the Eag1 K(+) channel were 0.265 +/- 0.413, 0.167 +/- 0.511, 2.673 +/- 2.988 and 2.815 +/- 2.901 in groups A, B, C and D, respectively, increased significantly in the latter two groups (P < 0.05). The positive rates of the protein expression of the Eag1 K (+) channel were significantly higher in groups C (88.9%) and D (86.7%) than in A (7.4%) and B (6.7%) (P < 0.05).

CONCLUSIONThe Eag1 K(+) channel might be involved in the pathophysiological processes of PCa, and is expected to be a valuable target for the diagnosis and treatment of PCa.

Ether-A-Go-Go Potassium Channels ; metabolism ; Humans ; Immunohistochemistry ; Male ; Prostate ; metabolism ; pathology ; Prostatic Neoplasms ; metabolism ; pathology ; RNA, Messenger ; genetics ; Reverse Transcriptase Polymerase Chain Reaction

Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screening of the genomic sequences of cardiac potassium ion channel genes, we found a single nucleotide C deletion mutation in the exon 3 of KCNH2 gene that co-segregates with the LQTS in this family. This mutation presumably resulted in a frameshift mutation, P151fs+15X. This study added a new genetic cause to the pool of mutations that lead to defected potassium ion channels in the heart.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/*genetics ; DNA Mutational Analysis ; Ether-A-Go-Go Potassium Channels/*genetics ; Exons ; Female ; Frameshift Mutation ; Genotype ; Humans ; Long QT Syndrome/*diagnosis/genetics ; Male ; Middle Aged ; Pedigree ; Republic of Korea ; Sequence Deletion

BACKGROUNDThe congenital Long QT syndrome (LQTS) is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval, syncope, ventricular arrhythmias, and sudden death. The chromosome 7-linked type 2 congenital LQTS (LQT2) is caused by gene mutations in the human ether-a-go-go-related gene (HERG).

METHODSA Chinese family diagnosed with LQTS were screened for KCNQ1, HERG and SCN5A, using polymerase chain reaction (PCR), direct sequencing, and clong sequencing. We also investigated the mRNA expression of the HERG gene.

RESULTSWe identified a novel I414fs + 98X mutation in the HERG gene. The deletion mutation of 14-bp in the first transmembrane segment (S1) introduced premature termination codons (PTCs) at the end of exon 6. This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels. But only the proband was symptomatic.

CONCLUSIONSWe found that the mRNA level of the HERG gene was significantly lower in I414fs + 98X carriers than in noncarriers. We found a novel I414fs + 98X mutation. The mRNA level supports that NMD mechanism might regulate the novel mutation.

Adult ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; Female ; Frameshift Mutation ; Humans ; Long QT Syndrome ; genetics ; RNA, Messenger ; analysis

OBJECTIVE: To investigate KCNQ1, KCNH2, KCNE1 and KCNE2 gene variants in the cases of sudden manhood death syndrome (SMDS). METHODS: One hundred and sixteen sporadic cases of SMDS and one hundred and twenty-five healthy controlled samples were enrolled. Genomic DNA was extracted from blood samples. Gene variants of KCNQ1, KCNH2, KCNE1 and KCNE2 were screened by direct sequencing. RESULTS: A total of 14 mutations and 14 SNP were detected. Two non-synonymous mutations of them were newfound. There was no non-synonymous mutation found in the control group. CONCLUSION There are KCNQ1, KCNH2, KCNE1 and KCNE2 gene variants found in Chinese SMDS cases. KCNQ1, KCNH2, KCNE1 and KCNE2 gene mutation may correlate partly with the occurrence of some cases of the SMDS in China.
Base Sequence ; Case-Control Studies ; China ; DNA Mutational Analysis ; Death, Sudden/ethnology* ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels/genetics* ; Humans ; KCNQ1 Potassium Channel/genetics* ; Long QT Syndrome ; Mutation ; Polymorphism, Single Nucleotide ; Potassium Channels ; Potassium Channels, Voltage-Gated/genetics*

OBJECTIVETo observe the effect of matrine on human ether à go-go related gene (HERG) potassium channels expressed in Chinese hamster ovary (CHO) cells and investigate whether HERG channel is a new target of the pharmacological effect of matrine on arrhythmia and tumor

METHODSHERG channel potassium current in CHO cell was recorded using whole-cell patch-clamp technique, and the influence of matrine on the current was explored.

RESULTSMatrine inhibited HERG potassium current in a dose-dependent manner, and the 50% inhibitory concentration (IC IC(50)) was 411±23 μmol/L. Matrine had no significant effect on the activation kinetics, and mainly blocked HERG channels in their closed state.

CONCLUSIONSThe blocking effect of matrine on HERG channels might be one of the mechanisms against arrythmias and tumors. Unlike most other blockers exerting blocking effect at the intracellular sites by entering the cell with the opening of HERG channel, matrine blocked HERG channels at the extracellular sites.

Alkaloids ; pharmacology ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; metabolism ; Humans ; Quinolizines ; pharmacology

OBJECTIVETo perform mutation analysis in a family with long QT syndrome.

METHODSThe medical record of the affected child and his parents were collected. The locus of gene associated with the long QT syndrome was mapped by linkage analysis. Mutation analysis was done by PCR-single strand conformation polymorphism (SSCP) and direct sequencing.

RESULTSA mutation (L539fs/47) and a SNP (L564L) were found in exon 7 of the KCNH2 gene of the proband. The mutation was from the father.

CONCLUSIONA novel mutation of L539fs/47 in the KCNH2 gene was identified in the LQTS family, which might be the disease-causing mutation for the family.

Base Sequence ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; Female ; Frameshift Mutation ; Humans ; Long QT Syndrome ; congenital ; genetics ; Male ; Molecular Sequence Data ; Pedigree ; Polymorphism, Single Nucleotide ; Young Adult