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Yanzong Yang,
Yiqing Yang,
Bo Liang, Jinqiu Liu,
Jun Li,
Morten Grunnet,
Søren-Peter Olesen,
Hanne B Rasmussen,
Patrick T Ellinor,
Lianjun Gao, [......],
Li Li,
Lei Wang,
Junjie Xiao,
Yi Liu,
Ying Liu,
Shulong Zhang,
Dandan Liang,
Luying Peng,
Thomas Jespersen,
Yi-Han Chen
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ABSTRACT: Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%-40% of cases. In the present study, a large Chinese family (four generations, 49 individuals) with autosomal-dominant LQTS was clinically evaluated. Genome-wide linkage analysis was performed by using polymorphic microsatellite markers to map the genetic locus, and positional candidate genes were screened by sequencing for mutations. The expression pattern and functional characteristics of the mutated protein were investigated by western blotting and patch-clamp electrophysiology. The genetic locus of the LQTS-associated gene was mapped to chromosome 11q23.3-24.3. A heterozygous mutation (Kir3.4-Gly387Arg) was identified in the G protein-coupled, inwardly rectifying potassium channel subunit Kir3.4, encoded by the KCNJ5 gene. The Kir3.4-Gly387Arg mutation was present in all nine affected family members and absent in 528 ethnically matched controls. Western blotting of human cardiac tissue demonstrated significant Kir3.4 expression levels in the cardiac ventricles. Heterologous expression studies with Kir3.4-Gly387Arg revealed a loss-of-function electrophysiological phenotype resulting from reduced plasma membrane expression. Our findings suggest a role for Kir3.4 in the etiology of LQTS.
The American Journal of Human Genetics 06/2010; · 10.60 Impact Factor
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Xiang Ren,
Chengqi Xu,
Chengxiong Zhan,
Yanzong Yang,
Lisong Shi,
Fan Wang,
Chuchu Wang,
Yunlong Xia,
Bo Yang,
Gang Wu,
Pengyun Wang,
Xiuchun Li,
Dan Wang,
Xin Xiong, Jinqiu Liu,
Ying Liu,
Mugen Liu,
Jingyu Liu,
Xin Tu,
Qing Kenneth Wang
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ABSTRACT: A frameshift mutation in the NPPA gene was identified in 1 family with atrial fibrillation (AF), however, further studies are needed to establish unequivocally the genetic association between NPPA and AF.
A case control association study and mutational analysis of NPPA were performed with 384 sporadic AF patients and 844 controls from a Chinese GeneID population. Genotyping was performed using High-Resolution Melt analysis. Mutational analysis was performed using direct DNA sequencing analysis.
Significant allelic association was detected between single nucleotide polymorphism (SNP) rs5063 and lone AF (p=0.015, OR=1.63; adjusted p=0.003). Genotypic association was significant assuming an additive or dominant model (adjusted p=0.005 and 0.007, respectively). Six new variants were identified in NPPA, including 2 in the 5'-UTR, 2 in the 3'-UTR, and 2 missense substitutions. Variants c.413T>C, c.*48G>A and c.*133G>T were not present in 844 controls, and the others were identified in controls.
Variants in NPPA confer risk of lone AF in a Chinese population. Thus, in addition to being a disease-causing gene with mutations identified in familial AF cases, NPPA is a susceptibility gene for lone AF.
Clinica chimica acta; international journal of clinical chemistry 04/2010; 411(7-8):481-5. · 2.54 Impact Factor
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Yiqing Yang,
Jun Li,
Xiaoping Lin,
Yanzong Yang,
Kui Hong,
Lei Wang, Jinqiu Liu,
Li Li,
Dinghong Yan,
Dandan Liang,
Junjie Xiao,
Hongmei Jin,
Jie Wu,
Yangyang Zhang,
Yi-Han Chen
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ABSTRACT: Accumulating evidence reveals that genetic variants play pivotal roles in familial atrial fibrillation (AF). However, the molecular defects in most patients with AF remain to be identified. Here, we report on three novel KCNA5 mutations that were identified in 4 of 120 unrelated AF families. Among them, T527M was found in two AF families, and A576V and E610K in two other AF families, respectively. The mutations T527M and A576V were also detected in 2 and 1 of 256 patients with idiopathic AF, respectively. The same mutations were not observed in 200 secondary AF patients and 500 controls. Functional analyses revealed consistent loss-of-function effects of mutant KCNA5 proteins on the ultrarapidly activating delayed rectifier potassium currents. These findings expand the spectrum of mutations in KCNA5 linked to AF and provide new insight into the molecular mechanism involved in AF.
Journal of Human Genetics 05/2009; 54(5):277-83. · 2.57 Impact Factor
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ABSTRACT: The purpose of this study is to test our hypothesis that injection of skeletal myoblasts (SkMbs) into viable tissue may alter impulse conduction but that injections into nonviable tissue (scar) will have negligible impact.
Myocardial infarction (MI) is a major public health problem. SkMb transplantation after MI has been shown to have some beneficial effect on hemodynamic function. Previous studies have indicated that SkMbs do not electrically couple with viable host myocardium in vivo.
We used optical mapping to measure impulse propagation and arrhythmia inducibility in the canine left ventricular wedge preparation with and without MI. MI was created by temporary ligation of a branch of the left anterior descending coronary artery (LAD) (7.0 +/- 3.8 ng/mL troponin 24 hours after MI). Labeled SkMbs (10(8) in 4 mL of serum-free basal solution) were injected from the epicardium (20-40 0.1 mL injections) into normal myocardium (n = 8) or the central zone of the MI (n = 6).
During endocardial pacing in the absence of MI, transmural conduction velocity was similar with (35.75 +/- 3.4 cm/s) and without (37.42 +/- 3.6 cm/s) SkMb transplantation. However, pacing from the epicardium resulted in conduction slowing in regions that were DiI-positive and associated with the expression of skeletal myosin (fast) but not connexin-43. In all preparations with MI (n = 13), abnormal impulse propagation was seen regardless of SkMb transplantation. Arrhythmias (at least one extra beat after standard programmed stimulation) occurred most frequently in preparations with MI independent of SkMb transplantation. In preparations without MI (n = 8), SkMb transplantation did not significantly increase arrhythmia inducibility.
We conclude that SkMbs transplanted into normal myocardium can cause abnormal impulse propagation. These data suggest that the location of SkMb transplantation may influence arrhythmia vulnerability associated with MI.
Heart Rhythm 05/2006; 3(4):452-61. · 4.10 Impact Factor
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ABSTRACT: Torsade de pointes (TdP), is often preceded by a short-long cycle length sequence. However, the causal relationship between the pause associated with a short-long cycle length sequence and TdP is not completely understood. This study tests the hypothesis that a pause enhances both dispersion of repolarization and EAD formation; however, EADs that form where APD is longest will be less likely to initiate TdP.
We used optical mapping to measure transmural action potentials from the canine left ventricular wedge preparation. D-sotalol and ATX-II were used to mimic LQT2 and LQT3, respectively. The pause significantly enhanced mean APD (from 356 +/- 20 to 381 +/- 25 msec in LQT2, P < 0.05; from 609 +/- 92 to 675 +/- 98 msec in LQT3, P < 0.05) and transmural dispersion (from 35 +/- 9 to 46 +/- 11 msec in LQT2, P < 0.05; from 121 +/- 85 to 171 +/- 98 msec in LQT3, P < 0.05) compared to steady state pacing. Under LQT3 condition EADs, EAD-induced triggered activity, and TdP were more likely to occur following a pause. Interestingly, the triggered beat following a pause always broke through at the region of maximum local repolarization gradient.
These data suggest that a pause accentuates transmural repolarization gradients and facilitates the formation of EADs and EAD-induced triggered activity. In contrast to our hypothesis, the findings of this study support the concept that M-cells (where APD is longest) can play an important role in both the origination of EAD-induced triggered activity and unidirectional block associated with TdP.
Journal of Cardiovascular Electrophysiology 09/2005; 16(9):981-7. · 3.06 Impact Factor
