The KCNQ potassium channels play a crucial role in modulating neural excitability, and their dysfunction is closely associated with epileptic disorders. While variants in KCNQ2 have been extensively studied, KCNQ3-related disorders have rarely been reported. With advances in next-generation sequencing technologies, an increasing number of cases of KCNQ3-related disorders have been identified. However, the correlation between genotype and phenotype remains poorly understood. In this study, we established a variant library consisting of 24 missense mutations in KCNQ3 and introduced these mutations into three different template types: KCNQ3, KCNQ3-A315T (Q3*), and KCNQ3-KCNQ2 tandem (Q3-Q2). We then analyzed the effects of these mutations on the KCNQ3 channel function using patch-clamp recording. The most informative parameter across all three backgrounds was the current density of the mutant channels. The current density patterns in the Q3* and Q3-Q2 backgrounds were similar, with most mutations resulting in an almost complete loss of function (LOF), they were concentrated in the pore-forming domain of KCNQ3. In contrast, mutations in the voltage-sensing domain or C-terminus did not show significant differences from the wild-type channel. Interestingly, these LOF mutations were typically associated with self-limited familial neonatal epilepsy, while neurodevelopmental disorders (NDD) were more closely associated with mutations that did not significantly differ from the wild-type. V_1/2, another important parameter of the electrophysiological properties, could not be accurately determined in the majority of KCNQ3 mutations due to its nearly complete LOF in the Q3* and Q3-Q2 backgrounds. Intriguingly, the V_1/2 of functional mutations were primarily leftward shifted, indicating a gain-of-function (GOF) effect, which was typically associated with NDD. In addition to previously reported mutations, we identified G553R as a novel GOF mutation. In the co-transfection background, parameters such as V_1/2 could be determined, but the dysfunctional effects of these mutations were mitigated by the co-expression of wild-type KCNQ3 and KCNQ2 subunits, resulting in no significant differences between most mutations and the wild-type channel. Furthermore, we applied KCNQ modulators to reverse the electrophysiological abnormalities caused by KCNQ3 variants. The LOF mutations were reversed by the application of Pynegabine (HN37), a KCNQ opener, while the GOF mutation responded well to Amitriptyline (AMI), a KCNQ inhibitor. These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making.
KCNQ3 Potassium Channel/genetics* ; Humans ; Mutation, Missense/genetics* ; KCNQ2 Potassium Channel/genetics* ; Patch-Clamp Techniques ; HEK293 Cells ; Animals ; Phenylenediamines/pharmacology* ; Carbamates

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

OBJECTIVETo explore the relationship between electrocardiographic (ECG) and genetic mutations of patients with hypertrophic cardiomyopathy (HCM), and early ECG changes in HCM patients.

METHODSClinical, 12-lead ECG and echocardiographic examination as well as genetic examinations were made in a three-generation Chinses HCM pedigree with 8 family members (4 males). The clinical characterization and ECG parameters were analyzed and their relationship with genotypes in the family was explored.

RESULTSFour missense mutations (MYH7-H1717Q, MYLK2-K324E, KCNQ1-R190W, TMEM70-I147T) were detected in this pedigree. The proband carried all 4 mutations and 5 members carried 2 mutations. Corrected QTc interval of KCNQ1-H1717Q carriers was significantly prolonged and was consistent with the ECG characterization of long QT syndrome. MYLK2-K324E and KCNQ1-R190W carriers presented with Q wave and(or) depressed ST segment, as well as flatted or reversed T waves in leads from anterolateral and inferior ventricular walls. ECG results showed ST segment depression, flat and inverted T wave in the gene mutation carriers with normal echocardiographic examination results. ECG and echocardiographic results were normal in TMEM70-I147T mutation carrier.

CONCLUSIONSThe combined mutations of the genes associated with cardiac ion channels and HCM are linked with the ECG phenotype changes in this HCM pedigree. The variations in ECG parameters due to the genetic mutation appear earlier than the echocardiography and clinical manifestations. Variation in ECG may become one of the indexes for early diagnostic screening and disease progression of the HCM gene mutation carriers.

Brugada Syndrome ; Cardiac Conduction System Disease ; Cardiac Myosins ; Cardiomyopathy, Hypertrophic ; Echocardiography ; Electrocardiography ; Exons ; Genetic Testing ; Genotype ; Humans ; KCNQ1 Potassium Channel ; Long QT Syndrome ; Mutation ; Mutation, Missense ; Myosin Heavy Chains ; Myosin-Light-Chain Kinase ; Pedigree ; Phenotype

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

Long QT syndrome (LQTS) is a genetically heterogeneous disorder associated with sequence variations in more than 10 genes; in some cases, it is caused by large deletions or duplications among the main, known LQTS-associated genes. Here, we describe a 14-month-old Korean boy with congenital hearing loss and prolonged QT interval whose condition was clinically diagnosed as Jervell and Lange-Nielsen syndrome (JLNS), a recessive form of LQTS. Genetic analyses using sequence analysis and multiplex ligation-dependent probe amplification (MLPA) assay revealed a large deletion spanning exons 7-10 as well as a frameshift mutation (c.1893dup; p.Arg632Glnfs*20). To our knowledge, this is the first report of a large deletion in KCNQ1 identified in JLNS patients. This case indicates that a method such as MLPA, which can identify large deletions or duplications needs to be considered in addition to sequence analysis to diagnose JLNS.
Adolescent ; Alleles ; Base Sequence ; Electrocardiography ; Exons ; Frameshift Mutation ; Heterozygote ; Humans ; Jervell-Lange Nielsen Syndrome/diagnosis/*genetics ; KCNQ1 Potassium Channel/*genetics ; Male ; Nucleic Acid Amplification Techniques ; Pedigree ; Sequence Analysis, DNA ; Sequence Deletion

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

PURPOSE: Patients with gestational diabetes mellitus (GDM) have been reported to exhibit the same genetic susceptibility as that observed in those with type 2 diabetes mellitus (T2DM). Recent polymorphism studies have shown that several genes are related to T2DM and GDM. The aim of this study was to examine whether certain candidate genes, previously shown to be associated with T2DM, also offer a specific genetic predisposition to GDM. MATERIALS AND METHODS: The current study was conducted in 136 Korean pregnant women, who gave birth at Gil Hospital, from October 2008 to May 2011. These study subjects included 95 subjects with GDM and 41 non-diabetic controls. We selected the specific genes of PPARgamma2, IGF2BP2, and KCNQ1 for study and amplified them using the polymerase chain reaction. This was followed by genotyping for single nucleotide polymorphisms. We then compared the genotype frequencies between patients with GDM and non-diabetic controls using the chi2 test. We obtained and analyzed clinical information using Student's t-test, and statistical analyses were conducted using logistic regression with SPSS Statistics software, version 19.0. RESULTS: Significant differences were observed in maternal age, body mass index, weight gain and weight at time of delivery between the groups compared. Among pregnant women, polymorphisms in PPARgamma2 and IGF2BP2 were shown to be highly correlated with GDM occurrence, whereas no correlation was found for KCNQ1 polymorphisms. CONCLUSION: Our results indicated that genetic polymorphisms could also be of value in predicting the occurrence and diagnosis of GDM.
Diabetes, Gestational/*genetics ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Humans ; KCNQ1 Potassium Channel/*genetics ; Logistic Models ; PPAR gamma/*genetics ; Polymorphism, Single Nucleotide ; Pregnancy ; RNA-Binding Proteins/*genetics ; Republic of Korea

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

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