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

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

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

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.
Ataxia ; Bartter Syndrome ; Brugada Syndrome ; Cardiovascular System ; Channelopathies* ; Diabetes Insipidus, Nephrogenic ; Diabetes Mellitus ; Endocrine System ; Epilepsy, Generalized ; Genetics ; Hypoglycemia ; Hypokalemic Periodic Paralysis ; Immune System ; Ion Channels ; Isaacs Syndrome ; Long QT Syndrome ; Membranes ; Migraine with Aura ; Myasthenia Gravis ; Nervous System ; Neuromyelitis Optica ; Organelles ; Polycystic Kidney Diseases ; Respiratory System ; Seizures, Febrile

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

The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc > or = 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/genetics ; Calcium Channels/genetics ; Child ; Child, Preschool ; Electrocardiography ; Heart Arrest/genetics/pathology ; Humans ; Infant ; KCNQ1 Potassium Channel/genetics ; KCNQ2 Potassium Channel/genetics ; Long QT Syndrome/*diagnosis/*genetics ; Middle Aged ; Mutation/*genetics ; NAV1.5 Voltage-Gated Sodium Channel/genetics ; Penetrance ; Potassium Channels, Inwardly Rectifying/genetics ; Republic of Korea ; Risk Factors ; Seizures/genetics/pathology ; Young Adult

Patients with long QT syndrome can sometimes present with a ventricular fibrillation (VF) storm. Catheter ablation of culprit premature ventricular complexes responsible for the triggering of the VF episodes may be required in rare cases of electrical storm that do not respond to conventional measures, and this can be life-saving. We describe a case of emergency catheter ablation in a young woman with a normal corrected QT interval, who presented with malignant VF storm for the first time. We also discuss the diagnostic and management challenges involved, as well as the value of genetic testing in refining the diagnosis.
Cardiology ; Catheter Ablation ; methods ; Electrocardiography ; methods ; Female ; Heart Arrest ; genetics ; therapy ; Heterozygote ; Humans ; Long QT Syndrome ; genetics ; Tachycardia, Ventricular ; therapy ; Treatment Outcome ; Ventricular Fibrillation ; therapy ; Ventricular Premature Complexes ; genetics ; therapy ; Young Adult

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

OBJECTIVETo construct the sodium channel gene SCN5A-delQKP1507-1509 mutation associated with congenital long QT syndrome, and its eukaryotic expression vector, and to examine the expression of mutation protein in human embryonic kidney (HEK) 293 cells.

METHODSEukaryotic expression vector PEGFP-delQKP-hH1 for SCN5A-delQKP1507-1509 mutation was constructed by rapid site-directed mutagenesis. HEK293 cells were transfected with the wild or mutant vector using lipofectamine, and then subjected to confocal microscopy. The transfected cells were immunostained to visualize intracellular expression of the mutant molecules.

RESULTSDirect sequence and electrophoresis analysis revealed 9 basic group absences at position 1507-1509. The delQKP1507-1509 mutation eukaryotic expression vector was expressed in HEK293 cells. Immunostaining of transfected cells showed the expression of both wild type and mutant molecules on the plasma membrane and there was no difference in the amount of protein, which suggested that the mutant delQKP1507-1509 did not impair normal protein expression in HEK293 cells.

CONCLUSIONSSuccessful construction of mutant SCN5AdelQKP1507-1509 eukaryotic expression vector and expression of SCN5A protein in HEK293 cells provides a basis for further study on the functional effects of congenital long QT syndrome as a cause of SCN5A mutation.

Blotting, Western ; HEK293 Cells ; Humans ; Long QT Syndrome ; congenital ; genetics ; Mutagenesis, Site-Directed ; NAV1.5 Voltage-Gated Sodium Channel ; analysis ; genetics ; physiology