Drug-induced QT-interval prolongation and recurrent torsade de pointes in a child with heterotaxy syndrome and KCNE1 D85N polymorphism

We present a child case of heterotaxy syndrome (asplenia syndrome) after Fontan procedure that showed extreme prolongation of QT interval and torsade de pointes (TdP) after administration of sodium channel blockers for paroxysmal atrial tachycardia. Despite low serum concentration of the drugs, QT prolongation persisted and TdP attacks with unconsciousness recurred, possibly in association with junctional bradycardia and myocardial damage although he had never experienced QT prolongation during bradycardia before. Temporal cardiac pacing via a venous route to exclude possible implication of bradycardia in induction of TdP was difficult to apply due to total cavopulmonary connection (TCPC) circulation. Continuous intravenous administration of low-dose isoproterenol was started but an appropriate heart rate for prevention of TdP was difficult to obtain. Finally, we were urged to conduct implantation of a DDD pacemaker combined with ICD surgically with epicardial leads, resulting in successful suppression of TdP and syncope. Screening of the genotype disclosed the KCNE1 D85N polymorphism, which is known as one of the typical disease-causing gene variants in long-QT syndrome (LQTS).     

Analysis of Gene Polymorphisms Associated with K+ Ion Circulation in the Inner Ear of Patients Susceptible and Resistant to Noise-induced Hearing Loss

Noise-induced hearing loss (NIHL) is one of the leading occupational health risks in industrialized countries. It results from an interaction between environmental and genetic factors, however the nature of the genetic factors contributing to NIHL has not yet been clarified. Here, we investigated whether genetic variations in 10 genes putatively involved in the potassium recycling pathway in the inner ear may influence susceptibility to noise. 99 SNPs were genotyped in Polish noise-exposed workers, categorized into susceptible and resistant subjects. The most interesting results were obtained for KCNE1 and KCNQ4 as we replicated associations that were previously reported in a Swedish sample set, hence confirming that they are NIHL susceptibility genes. Additionally we report significant associations in GJB1 , GJB2 , GJB4 , KCNJ10 and KCNQ1 , however due to the lack of replication in the Swedish sample set, these results should be seen as suggestive.     

Common candidate gene variants are associated with QT interval duration in the general population

Objectives. QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30–40% of the QT‐interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population‐based sample. Methods. We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI‐TOF mass spectrometry. ECG parameters were measured from digital 12‐lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. Results. The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT_Nc interval (P = 3.6 × 10^?11) in gender‐pooled analysis. In agreement with previous studies, we replicated the association with QT_Nc interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P = 4.7 × 10^?5], KCNH2 K897T [?2.6 ms (SE 0.5) or ?0.14 SD, P = 2.1 × 10^?7] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P = 3.2 × 10^?24] under additive models. Conclusions. We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age‐, gender‐ and heart rate‐adjusted QT interval and could thus modulate repolarization‐related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.     

Targeting of Kv7.5 (KCNQ5)/KCNE channels to surface microdomains of cell membranes

Background: Kv7.5 (KCNQ5) channels conduct M‐type potassium currents in the brain, are expressed in skeletal muscle, and contribute to vascular muscle tone. Methods: We coexpressed Kv7.5 and KCNE1–3 peptides in HEK293 cells and then analyzed their association using electrophysiology and co‐immunoprecipitation, assessed localization using confocal microscopy, examined targeting of the oligomeric channels to cholesterol‐rich membrane surface microdomains using lipid raft isolation, and evaluated their membrane dynamics using fluorescence recovery after photobleaching (FRAP). Results: Kv7.5 forms oligomeric channels specifically with KCNE1 and KCNE3. The expression of Kv7.5 targeted to cholesterol‐rich membrane surface microdomains was very low. Oligomeric Kv7.5/KCNE1 and Kv7.5/KCNE3 channels did not localize to lipid rafts. However, Kv7.5 association impaired KCNE3 expression in lipid raft microdomains. Conclusions: Our results indicate that Kv7.5 contributes to the spatial regulation of KCNE3. This new scenario could greatly assist in determining the physiological relevance of putative KCNE3 interactions in nerve and muscle. Muscle Nerve 45: 48–54, 2012     

心肌钾离子通道β亚单位基因KCNE1多态S38G与心房颤动的关系

目的:探讨我国汉族人群心肌钾离子通道β亚单位基因KCNE1多态S38G与心房颤动(房颤)发生间的关系,并分析KCNE1-S38G在该人群中的分布特点。方法:入选房颤患者111例(病例组)及健康者101名(对照组),病例组根据基础疾病不同又分成4个亚组:孤立性房颤、高血压合并房颤、冠心病合并房颤及高血压冠心病合并房颤。采用PCR-DNA测序方法检测病例及对照组KCNE1基因编码序列,并进行统计分析。结果:病例组与对照组间,KCNE1-S38G的3种基因型频率为A/A(6.3%比11.9%)、A/G(36.9%比28.7%)、G/G(56.8%比59.4%)及A、G等位基因频率(24.8%和75.2%比26.2%和73.8%),其存在一定差异,但无显著性。各房颤亚组间比较也无显著差异。病例组各基因型间的校正QT间期(QTc)值无显著差异。结论:KCNE1-S38G在房颤患者中占一定优势,但与正常对照组相比无显著差别。KCNE1-S38G多态性位点可能存在种族、地区差异。     

KCNE2对Kv4.3通道功能的调节作用

目的研究KCNE2对人类心肌细胞瞬间外向钾电流的主要α亚基-Kv4.3功能的调节。方法通过基因转染技术将Kv4.3或Kv4.3与KCNE2cDNA转入COS-7细胞株,采用膜片钳全细胞记录方式记录通道电流。结果KCNE2对Kv4.3功能有明显调控作用:减小Kv4.3通道电流密度;Kv4.3单独表达组通道电流密度为375.13±112.87pA/pF(n=11),KCNE2与Kv4.3共表达组电流密度为152.96±33.71pA/pF(n=16);减慢Kv4.3通道激活和衰减,在 60mV电压刺激下通道激活达峰值的时间由4.82±0.32ms(n=11)延长至20.41±2.13ms(n=16),P<0.05;通道电压依赖性失活发生正向移位,半数失活电压由-53.62±1.24mV(n=8)移至-46.58±1.6mV(n=10);通道从失活中恢复的速度加快,恢复时间常数由193.43±17.98ms缩短137.71±18.29ms,(n=7,P<0.05)。结论KCNE2可能作为人类心肌细胞膜Kv4.3钾离子通道一个重要的辅助亚基-β亚基参与Ito通道功能的调节。     

KCNE1基因与孤立性心房颤动的关系

目的　探讨KCNE1基因与孤立性心房颤动的关系。方法　随机收集 94例孤立性心房颤动患者(病例组 )和 130名无血缘关系的健康者 (对照组 ) ,采用PCR直接测序的方法测定KCNE1序列。在获得G116A多态性的基础上 ,采用关联研究分析KCNE1基因型与心房颤动表现型的关系。结果　病例组和对照组GA、GG和AA基因型的差异无显著性 (GA :4 8对 37,GG :72对 5 4 ,AA :10对 3;χ2 =1.5 6 8,P >0 .0 5 )。结论　KCNE1基因与孤立性心房颤动的发病无关。     

Single Nucleotide Polymorphisms and Haplotype of Four Genes Encoding Cardiac Ion Channels in Chinese and their Association with Arrhythmia

Background : Many studies revealed that variations in cardiac ion channels would cause cardiac arrhythmias or act as genetic risk factors. We hypothesized that specific single nucleotide polymorphisms in cardiac ion channels were associated with cardiac rhythm disturbance in the Chinese population. Method : We analyzed 160 nonfamilial cardiac arrhythmia patients and 176 healthy individuals from which 81 individuals were selected for association study, and a total of 19 previously reported SNPs in four cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1) were genotyped. Results : The frequency of KCNQ1 1638G>A, as well as the haplotype harboring KCNQ1 1638A, KCNQ1 1685 + 23G and 1732 + 43T (haplotype AGT) was significantly higher in healthy controls than in arrhythmia patients. This finding implicated that this haplotype (AGT) might be a protective factor against arrhythmias. Conclusions : Our study provided important information to elucidate the effect of SNPs of cardiac ion channel genes on channel function and susceptibility to cardiac arrhythmias in Chinese population.     

Expression of voltage-dependent potassium channels in first trimester human placentae

Potassium channel α-subunits encoded by KCNQ1-5 genes form voltage-dependent channels (K_V7), modulated by KCNE1-5 encoded accessory proteins. The aim was to determine KCNQ and KCNE mRNA expression and assess protein expression/localisation of the KCNQ3 and KCNE5 isoforms in first trimester placental tissue. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks' (early TOP) and >10 weeks' (mid TOP) gestations. KCNQ1-5 expression was unchanged during the first trimester. KCNE5 expression increased in mid TOP vs. early TOP samples (P = 0.022). This novel study reports mRNA and protein expression of K_V7 channels in first trimester placentae.     

Mink相关肽1对超极化激活的环核苷酸门控的阳离子通道4电生理特性的调节

目的:评价Mink相关肽1(KCNE2或MiRP1)对异源转染的中国仓鼠卵巢(CHO)细胞上的超极化激活的环核苷酸门控的阳离子通道(HCN)4电生理特性的影响。方法:将成功转染HCN4的CHO细胞(n=12)及共转染HCN4+KCNE2的CHO细胞(n=13),即将KCNE2质粒脱氧核糖核酸(DNA)单独转染或和HCN4质粒DNA共转染CHO-K1细胞,用标准微电极全细胞膜片钳记录细胞膜上的HCN4电流。结果:KCNE2对HCN4电流大小的影响:无论是在单独转染HCN4,还是HCN4和KCNE2共转染的CHO细胞中,均能检测到电流的表达。HCN4和KCNE2共转染的细胞中所检测到的电流密度,显著大于单独的HCN4转染细胞中的电流密度,差异有统计学意义(P<0.01)。KCNE2对HCN4激活动力学的影响:KCNE2和HCN4共转染后,其代表通道激活动力学的指标:激活时间常数(Tau)较单独转染HCN4时明显减小,差异有统计学意义(P<0.05)。KCNE2对HCN4激活的电压依赖性的影响:从稳态激活曲线中发现,无论是通道激活50时的脉冲电压(V1/2)还是倾斜因子(S),在HCN4与HCN4+KCNE2两组之...