OBJECTIVETo search for the mutations of potassium voltage-gated channel, KQT-like subfamily member 1(KCNQ1) gene in 31 Chinese long QT syndrome(LQTS) families.

METHODSDue to the genetic heterogeneity, the genotype of patients was first predicted based on the spectrum of ST-T-wave patterns on ECG. Ten of 31 probands were considered as LQT1. Then the mutation of KCNQ1 gene was screened by the polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) technique combined with DNA sequencing in all members of these 10 families. To avoid omitting some LQT1 patients without typical characteristics and also to do methodological comparison, the mutations of KCNQ1 gene on 16 exons were screened by PCR and direct DNA sequencing in the rest 21 non-LQT1 probands only. Co-segregation analysis was carried out after the finding of an abnormal sequence. In case that the abnormality existed in patients only, the test of such exon was performed in 50 irrelevant normal individuals.

RESULTSTwo missense mutations and three single nucleotide polymorphisms (SNPs) were found in the LQT1 predicted families. The two mutations were S277L (1 family) and G306V (1 family) in exon 5 and were not reported previously. Three polymorphisms were 435C-->T (7 families), 1632C-->A (1 family), and IVS1+9 C-->G (3 families). Only a splice mutation IVS1+5G-->A (2 families) and a polymorphism IVS10+18C-->T (1 family) were found in the non-LQT1 predicted probands. All three mutations were localized within the functional domain of KCNQ1 and were co-segregated with the disease, and were not found in 50 normal individuals.

CONCLUSIONTwo novel missense mutations, 1 splice mutation and four SNPs on KCNQ1 gene were found in the 31 LQTS families. Combined with ECG-based genotype prediction, PCR-SSCP could find most mutations on KCNQ1 and be a simple and economic method for screening LQTS.

Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; KCNQ Potassium Channels ; KCNQ1 Potassium Channel ; Long QT Syndrome ; genetics ; Male ; Middle Aged ; Mutation ; Potassium Channels ; genetics ; Potassium Channels, Voltage-Gated

OBJECTIVETo determine mutations of two common potassium channel subunit genes KCNQ1, KCNH2 causing long QT syndrome (LQTS) in the Chinese.

METHODSThirty-one Chinese LQTS pedigrees were characterized for mutations in the two LQTS genes, KCNQ1 and KCNH2, by sequencing.

RESULTSTwo novel KCNQ1 mutations, S277L in the S5 domain and G306V in the channel pore, and two novel KCNH2 mutations, L413P in the transmembrane domain S1 and L559H in the transmembrane domain S5 were identified. The triggering factors for cardiac events developed in these mutation carriers included physical exercise and excitation. Mutation L413P in KCNH2 was associated with the notched T wave on ECGs. Mutation L559H in KCNH2 was associated with the typical bifid T wave on ECGs. Mutation S277L in KCNQ1 was associated with a high-amplitude T wave and G306V was associated with a low-amplitude T wave. Two likely polymorphisms, IVS11 + 18C > T in KCNQ1 and L520V in KCNH2 were also identified in two LQTS patients.

CONCLUSIONSThe mutation rates for both KCNQ1 (6.4%) and KCNH2 (6.4%) are lower in the Chinese population than those from North America or Europe.

Asian Continental Ancestry Group ; Cation Transport Proteins ; China ; DNA-Binding Proteins ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; Female ; Humans ; KCNQ Potassium Channels ; KCNQ1 Potassium Channel ; Long QT Syndrome ; genetics ; Male ; Mutation ; Potassium Channels ; genetics ; Potassium Channels, Voltage-Gated ; Trans-Activators ; Transcriptional Regulator ERG

OBJECTIVECongenital long QT syndrome (LQTS) is an inherited disorder of cardiac repolarization characterized by prolongation of QT interval and polymorphic ventricular tachycardia torsade de pointes (TdP) in the electrocardiogram (ECG). Clinical symptoms include recurrent syncope, seizure or even sudden death. It is caused by mutations of at least seven genes, six of them encoding ion channels that determine the duration of ventricular action potentials. One of these genes, KCNQ1, encodes an alpha-subunit of cardiac slowly activated delayed rectifier potassium channel. Patients carrying mutations of KCNQ1 are named as LQT1, which accounts for 42% of patients with LQTS. This study sought to analyze the clinical data of Chinese with LQTS and to screen for the mutations of KCNQ1.

METHODSThe universally accepted phenotypic criteria of LQTS was used for identification of probands. There were six families with LQTS. They were enrolled in this study. Clinical and ECG data of each family member were recorded. Genomic DNA was prepared from peripheral blood lymphocytes. Polymerase chain reaction-single strand conformation polymorphism analysis was used to screen for mutations throughout the whole coding region of KCNQ1 and DNA sequencing was performed to determine the exact mutation site.

RESULTSThere were totally 13 patients in the six LQTS families. Five were male and eight female. One suffered from sudden death, 10 had syncope and 2 were asymptomatic. Eleven of the 13 patients had ECG data. Their QT and QTc (mean +/- SD) were (0.460 +/- 0.058) s and (0.516 +/- 0.058) s, respectively. TdP was observed in 3 patients (27%) during the syncope attack. By PCR-SSCP analysis, two novel KCNQ1 deletion mutations 356-357 Delta QQ and 626-631 Delta GSGGPP were identified in 7 patients of 2 families. None of 50 normal individuals carried these mutations, indicating these two mutations were likely to cause the disease. In addition, P448R was found in one affected and some unaffected members in other two families and in 7 of 50 (14%) normal individuals, indicating that this might be a polymorphism. All the three mutations located in C-terminal domain of KCNQ1 protein.

CONCLUSIONSTwo novel deletion mutations and one novel polymorphism of KCNQ1 gene were identified among 6 Chinese families with LQTS.

Adolescent ; Adult ; Base Sequence ; Child ; DNA ; chemistry ; genetics ; DNA Mutational Analysis ; Electrocardiography ; Female ; Humans ; KCNQ Potassium Channels ; KCNQ1 Potassium Channel ; Long QT Syndrome ; genetics ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Pedigree ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Single-Stranded Conformational ; Potassium Channels ; genetics ; Potassium Channels, Voltage-Gated

To study the functional expression of KCNQ gene in outer hair cells (OHCs) and Deiters' cells, the effects of linopirdine on the whole cell K(+) current were investigated by using the whole cell variant of patch clamp technique in the present study. The outward tetraethylammonium (TEA)-sensitive K(+) current and the inward K(+) current (I(Kn)) in OHCs were recorded and measured before and after the administration of linopirdine. Simultaneously, the whole cell currents in Deiters?cells were also observed in normal solution and in the presence of linopirdine. After the application of 100 micromol/L linopirdine to OHCs, the peak K(+) current was reversibly blocked and the late K(+) current was partly reduced. In addition, the decay time constant of the TEA-sensitive K(+) current was prolonged in the presence of 100 micromol/L linopirdine. The inward current in OHCs was totally inhibited after the superfusion of 100 mmol/L and 200 micromol/L linopirdine respectively. The outward rectifier K(+) current (Ik) was the dominant K(+) current in the whole cell currents in Deiters' cells. In the presence of 200 micromol/L linopirdine, the I(K) current was not significantly affected. Our findings demonstrate that the KCNQ heteromeric or homomeric potassium channel is possibly the molecular basis for the peak outward K(+) current and that the inward I(Kn) current is mediated by KCNQ potassium channel. KCNQ potassium channel in OHCs can not only permit the K(+) efflux but also limit the depolarization. In the present study, no expression of KCNQ potassium channel is found in Deiters' cells.
Animals ; Cochlea ; cytology ; Electrophysiology ; Guinea Pigs ; Hair Cells, Auditory, Outer ; cytology ; metabolism ; Indoles ; pharmacology ; KCNQ Potassium Channels ; Patch-Clamp Techniques ; Potassium Channel Blockers ; pharmacology ; Potassium Channels ; physiology ; Potassium Channels, Voltage-Gated ; genetics ; Pyridines ; pharmacology ; Vestibular Nucleus, Lateral ; cytology

Injury or inflammation induces release of a range of inflammatory mediators. Bradykinin is one of the most important inflammatory mediators and plays a crucial role in mediating inflammatory pain. It is well known that multiple ion channels located in the nociceptors participate in pain sensation. Recent studies demonstrate an important role of bradykinin in regulating the function and expression of pain-related ion channels. This paper summarizes the recent advances in the understanding of the role of bradykinin in modulation of the channels and discusses future possibilities in the treatment of inflammatory pain.
Acid Sensing Ion Channels ; Animals ; Bradykinin ; pharmacology ; physiology ; Humans ; Inflammation ; complications ; Inflammation Mediators ; pharmacology ; physiology ; Ion Channels ; KCNQ Potassium Channels ; metabolism ; physiology ; Nerve Tissue Proteins ; metabolism ; Pain ; etiology ; metabolism ; physiopathology ; Receptors, AMPA ; metabolism ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Receptors, Purinergic P2X3 ; metabolism ; Sodium Channels ; metabolism ; TRPA1 Cation Channel ; TRPV Cation Channels ; metabolism ; physiology ; Transient Receptor Potential Channels ; metabolism ; physiology

OBJECTIVETo diagnose a Chinese benign familial neonatal convulsions (BFNC) family at the level of gene and investigate its molecular pathogenesis.

METHODSAll family members were studied by clinical examinations and linkage analysis. Mutation analysis of KCNQ2 gene was made by means of polymerase chain reaction (PCR)-direct sequencing and PCR-single strand conformation polymorphism (SSCP) in the proband, 16 family members and 72 unrelated normal individuals.

RESULTSLinkage analysis hinted the linkage of BFNC to KCNQ2, while the linkage to KCNQ3 was excluded. Mutation 1931delG of KCNQ2 gene was found in the proband by DNA-direct sequencing. The same SSCP variant as the proband's was showed in the rest affected members of this family but not in the unaffected members of this family and all of the 72 unrelated normal individuals.

CONCLUSION1931delG of KCNQ2 gene can cause BFNC in China and is novel mutation. The combination of linkage analysis and gene analysis is useful for gene diagnosis.

Epilepsy, Benign Neonatal ; genetics ; Female ; Genetic Linkage ; Humans ; Infant, Newborn ; KCNQ2 Potassium Channel ; KCNQ3 Potassium Channel ; Mutation ; Potassium Channels ; chemistry ; genetics ; Potassium Channels, Voltage-Gated

Epilepsy is one of the most common and debilitating neurological diseases that affects more than 40 million people worldwide. Genetic factors contribute to the pathogenesis of epilepsy. Molecular genetic studies have identified 15 disease-causing genes for epilepsy. The majority of the genes encode ion channels, including voltage-gated potassium channels KCNQ2 and KCNQ3, sodium channels SCN1A, SCN2A, and SCN1B, chloride channels CLCN2, and ligand-gated ion channels CHRNA4, CHRNB2, GABRG2, and GABRA1. Interestingly, non-ion channel genes have also been identified as epilepsy genes, and these genes include G-protein-coupled receptor MASS1/VLGR1, GM3 synthase, and proteins with unknown functions such as LGI1, NHLRC1, and EFHC1. These studies make genetic testing possible in some patients, and further characterization of the identified epilepsy genes may lead to the development of new drugs and new treatments for patients with epilepsy.
Chloride Channels ; genetics ; Epilepsies, Myoclonic ; genetics ; Epilepsy ; genetics ; Epilepsy, Absence ; genetics ; Humans ; KCNQ2 Potassium Channel ; genetics ; KCNQ3 Potassium Channel ; genetics ; NAV1.1 Voltage-Gated Sodium Channel ; NAV1.2 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins ; genetics ; Sodium Channels ; genetics

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

Codon, Nonsense ; Epilepsy ; genetics ; Humans ; KCNQ2 Potassium Channel ; genetics

Epilepsy is a group of disorders characterized by recurrent seizures. The etiologies of idiopathic epilepsy commonly have a genetic basis. Gene mutations causing several of the inherited epilepsies have been mapped. In this review, the authors summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, emphasizing how genetic defects may correlate with the pathophysiological mechanisms of brain hyperexcitability and gene defects can lead to epilepsy by altering multiple and diverse aspects of neuronal function.
Epilepsy ; genetics ; Humans ; KCNQ2 Potassium Channel ; Mutation ; NAV1.1 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins ; genetics ; Potassium Channels ; genetics ; Potassium Channels, Voltage-Gated ; Receptors, Nicotinic ; genetics ; Research ; trends ; Research Design ; Sodium Channels ; genetics ; Voltage-Gated Sodium Channel beta-1 Subunit