Mutations In KCNQ1 Gene Research Articles

GW24-e0353 A novel mutation R397Q in KCNQ1 gene caused dilated cardiomyopathy with ventricular tachycardia and prolonged QT interval

ObjectivesDilated cardiomyopathy (DCM) is a major cause of sudden cardiac death with lethal ventricular arrhythmias. So far, the genetic mutations of DCM are mainly related to the sarcomeric protein, and...

Angeborenes Langes QT-Syndrom

Inherited long QT syndrome (LQTS) is characterized by a prolonged ventricular repolarization (QTc interval) and symptoms (syncope, sudden cardiac arrest) due to polymorphic ventricular arrhythmias. As of today, 13 different cardiac ion channel genes have been associated with congenital LQTS. The most common ones are due to KCNQ1 (LQT-1), KCNH2 (LQT-2), and SCN5A (LQT-3) gene mutations and account for up to 75% of cases. Typical clinical findings are an increased QT interval on the surface electrocardiogram, specifically altered T wave morphologies, polymorphic ventricular arrhythmias, or an indicative family history. Recently, in the HRS/EHRA expert consensus statement, comprehensive genetic testing of major LQTS genes was recommended for index patients for whom there is a strong clinical suspicion of LQTS. Overall, antiadrenergic therapy, in particular β-receptor blockers, has been the mainstay of therapy and has significantly reduced cardiac events. For high-risk patients, an implantable cardioverter defibrillator (ICD) is recommended. Importantly, lifestyle modification and avoidance of arrhythmia triggers are additional important approaches.

Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing

BackgroundClassic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. Methods and ResultsOne hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. ConclusionsIncidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis.

ORAL PRESENTATION

ORAL PRESENTATION

AS-022 Effect of Triple Antiplatelet Therapy on Small Coronary Artery Treated with Zotarolimus Eluting Stent

Introduction: Congenital long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy and one of the leading causes of sudden cardiac death in the young. Disease prevalence is estimated nearly 1 in 3000 people. There have been impressive advancements in pathogenic mechanisms for LQTS, which enable us to classify the disease into different types. Long QT syndrome type 1 is triggered by exercise, associated with mutations in KCNQ1 gene which is responsible for slow component of the delayed rectifier repolarizing current (IKS). We report the case of type 1 LQTS based on the result of epinephrine QT stress testing. Case: A 20-year old man has been presented with syncope and seizure like episodes since he was 3 years old. These episodes usually lasted for 5-10 minutes and spontaneously subsided. His EKG showed a sinus rhythm with prolong QTc interval of 476ms. Diagnosed with congenital LQTS, he took propranolol and atenolol, which were effective until 19 years of age. However, after that, he felt fluttering and dizziness again. In most cases, this symptom developed after exercise, especially running. His family history was not significant for syncope or premature sudden death. His lab findings, 2-D echo and holter EKG test results were also unremarkable. Thus we conducted an epinephrine infusion test according to the protocol of Shimizu and Antzelevitch. Immediately after the bolus injection of 0.1μg/kg of epinephrine, the EKG showed marked prolongation of QTc from 512ms to 617ms. When he was challenged with isoproterenol after head up tilt test, blood pressure decreased accompanied by dizziness and nausea and T-alterans EKG pattern, Putting together his clinical history and provocation results, we made the diagnosis of a long QT syndrome, probably type 1. He was advised to avoid strenuous exercise and ensure regular full doses of beta-blocker. Conclusion: In this case, the most likely cause of the QT prolongation is exercise, but his several holter EKG indicated no ventricular tachycardia. A provocative test using epinephrine showed the marked increase in QTc interval. Therefore, the diagnosis is LQTS type 1, but further genetic tests are required to confirm that.

Disease Characterization of Long QT Syndrome Using iPS Cell-Derived Cardiomyocytes

Long QT syndrome (LQTS) is well characterized inheritable, life threatening disease, and often related to large pedigrees of family history. The present study established induced pluripotent stem cell (iPSC) from the patients with LQTS, and investigated whether the LQTS patient-derived iPSCs can be utilized for disease characterization, and drug response. We reprogrammed patient somatic cells, differentiated cardiomyocytes and examined electrophysiological properties. Genotype analysis showed the heterozygote mutation in KCNQ1 gene, 1893delC, indicating that this patient was type 1 LQTS. Drug response examination using multi-electrode analysis (MEA) revealed the LQTS-iPSC-derived cardiomyocytes revealed IKs disturbance, but not IKr. Electrophysiological recording confirmed 1893delC has a dominant negative role in IKs channel function by trafficking defect. Isoproterenol induced ventricular tachycardia-like arrhythmia. This study provides the evidences that iPSCs can be utilized for characterization, drug response, and diagnosis for patients with LQTS to conduct medical therapies.

A Weak Dominant Negative Mutation of KCNQ1-G269S Affects PKA-Mediated Up-Regulation of IKs Channels and Causes Adrenergic Triggered Long QT Syndrome

Congenital Long QT syndrome (LQTS) is an ion channelopathy characterized by QT interval prolongation in the ECG and ventricular tachyarrhythmias. It is caused by at least 13 types of gene mutations, among which the KCNQ1 gene mutation is most frequent and responsible for the LQT1. We identified a KCNQ1-G269S mutation in 11 patients from 4 families. Clinical data showed that most of patients were asymptomatic. Exercise stress test, however, prolonged their QTc intervals significantly. We engineered a G269S mutation by using PCR based mutagenesis and transfected into CHO or HEK293 cells together with KCNE1 by lipofectamine method. The whole cell IKs mutant currents were checked up using the patch-clamp technique. Co-expression of G269S decreased IKs currents in a mutant concentration-dependent manner, shifted the I-V relationship of IKs currents to more depolarizing direction, and accelerated the deactivation time of the currents. We found that G269S was a trafficking-refractory mutation and that the IKs reconstituted by G269A alone or the co-expression of wild type (WT)+G269S lost their response to β-adrenergic stimulation. Thus G269S mutation (1) exerted weak dominant-negative suppression effects on WT KCNQ1 channels; (2) coassembled with WT subunits to form tetramers and altered their gating kinetics and (3) may be associated with exercise-dependent unmasking of QTc prolongation.

Mechanistic basis for the pathogenesis of long QT syndrome associated with a common splicing mutation in KCNQ1 gene

Mutations in KCNQ1, the gene encoding the delayed rectifier K + channel in cardiac muscle, cause long QT syndrome (LQTS). We studied 3 families with LQTS, in whom a guanine to adenine change in the last base of exon 7 (c.1032G > A), previously reported as a common splice-site mutation, was identified. We performed quantitative measurements of exon-skipping KCNQ1 mRNAs caused by this mutation using real-time reverse transcription polymerase chain reaction. Compared with normal individuals who have minor fractions of splicing variants (Δ7–8: 0.1%, Δ8: 6.9%, of total KCNQ1 transcripts), the affected individuals showed remarkable increases of exon-skipping mRNAs (Δ7: 23.5%, Δ7–8: 16.8%, Δ8: 4.5%). Current recordings from Xenopus laevis oocytes heterologously expressing channels of wild-type (WT) or exon-skipping KCNQ1 (Δ7, Δ7–8, or Δ8) revealed that none of the mutants produced any measurable currents, and moreover they displayed mutant-specific degree of dominant-negative effects on WT currents, when co-expressed with WT. Confocal microscopy analysis showed that fluorescent protein-tagged WT was predominantly expressed on the plasma membrane, whereas the mutants showed intracellular distribution. When WT was co-expressed with mutants, the majority of WT co-localized with the mutants in the intracellular space. Finally, we provide evidence showing direct protein–protein interactions between WT and the mutants, by using fluorescence resonance energy transfer. Thus, the mutants may exert their dominant-negative effects by trapping WT intracellularly and thereby interfering its translocation to the plasma membrane. In conclusion, our data provide a mechanistic basis for the pathogenesis of LQTS caused by a splicing mutation in KCNQ1.

Effect of physical training on ventricular repolarization in type 1 long QT syndrome: a pilot study in asymptomatic carriers of the G589D KCNQ1 mutation

High-intensity physical exercise and competitive sports have been traditionally avoided in long QT syndrome. However, endurance training increases vagal activity and thus may improve cardiac electrical stability in healthy subjects. We hypothesized that controlled submaximal endurance training would not adversely affect ventricular repolarization in asymptomatic carriers of a KCNQ1 gene mutation of type 1 long QT syndrome (LQT1). Previously, sedentary carriers of a missense mutation of KCNQ1 gene (LQT1, n=7) and healthy controls (n=8) exercised on a bicycle ergometer 3-4 times a week, 30 min a day at 60-75% of maximal heart rate (HR) for a maximum of 3 months. Body surface potential mapping (BSPM) was recorded and QT intervals were determined automatically from 14 channels over the left chest area. Maximal work capacity increased by 4+/-1% in LQT1 and by 14+/-2% in controls (both P<0.05), and left ventricular (LV) mass by 8+/-1% and 9+/-1%, respectively (P<0.05). Resting corrected QT interval shortened by 10+/-1% (P<0.05) and QT interval dispersion by 25+/-9% (P<0.05) in LQT1, but not significantly in controls. QT intervals at specified HRs during workload and recovery phases were not changed in either group. In this pilot study of asymptomatic carriers of a KNCQ1 gene mutation, submaximal endurance training did not harmfully affect arrhythmia risk markers. Confirmatory studies in a broader spectrum of LQT1 genotypes are needed before any generalization can be made.

Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome.

Recent data showed that long QT syndrome (LQTS) patients with mutations in the pore region of the HERG (LQT2) gene have significantly higher risk of cardiac events than subjects with mutations in the non-pore region. The aim of this study was to determine whether there is an association between the location of mutations in the KCNQ1 gene and cardiac events in LQT1 patients. The study population consisted of 294 LQT1 patients with KCNQ1 gene mutations. Demographic, clinical, and follow-up information was compared among subjects with different locations of KCNQ1 mutations defined as pre-pore region including N-terminus (1-278), pore region (279-354), and post-pore region including C-terminus (>354). Cardiac events observed during follow-up from birth until age of last contact or age 40 years were defined as syncope, cardiac arrest, or sudden death. There were 164 (56%) LQT1 patients with pre-pore mutations, 101 (34%) with pore mutations, and 29 (10%) with post-pore mutations. QTc duration did not differ significantly among the three subgroups (mean QTc = 494, 487, and 501 ms, respectively). There was no significant difference between groups with regard to the risk of cardiac events by age 40 years. There are no significant differences in clinical presentation, ECG parameters, and cardiac events among LQT1 patients with different locations of KCNQ1 mutations. These findings indicate that factors other than location of mutation influence clinical phenotype in patients with LQT1 mutations.

Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome

KCNQ1 is a gene encoding an α subunit of voltage-gated cardiac K+ channels, with properties similar to the slowly activating delayed rectifier K+ current, and one of the genes causing long QT syndrome (LQTS). However, genotype–phenotype correlations of the KCNQ1 gene mutations are not fully understood. The aims of this study were to identify a mutation in the KCNQ1 gene in patients with LQTS, and to characterize the clinical manifestations and electrophysiological properties of the mutation. We screened and identified mutations by PCR, single-strand conformational polymorphism analysis and DNA sequencing. We identified a novel mutation [Phe193Leu (F193L)] in the KCNQ1 gene in one family with LQTS. The patients with this mutation showed a mildly affected phenotype. The proband was a 17-year-old girl who had a prolonged QT interval. Her elder brother, father and paternal grandmother also had the mutation. None of them had any history of syncope. Sudden death was not found in this family. Next, we studied the electrophysiological characteristics of the F193L mutation in the KCNQ1 gene using the expression system in Xenopus oocytes and the two-microelectrode voltage-clamp technique. Co-expression of F193L KCNQ1 with the K+ channel minK suppressed peak (by 23.3%) and tail (by 38.2%) currents compared with those obtained by the combination of wild-type (WT) KCNQ1 and minK. Time constants of current activation in F193L KCNQ1 and F193L KCNQ1+minK were significantly slower than those of WT KCNQ1 and WT KCNQ1+minK. This electrophysiological study indicates that F193L causes less severe KCNQ1 current suppression, and thereby this mutation may result in a mildly affected phenotype.

Location of mutation in the KCNQ1 gene does not influence outcome of long QT syndrome patients

Location of mutation in the KCNQ1 gene does not influence outcome of long QT syndrome patients