Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.
Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.
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DOI：
10.1016/j.hrthm.2011.02.021
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发表时间：
2011-07
期刊：
影响因子：
5.5
通讯作者：
Ackerman, Michael J.
中科院分区：
文献类型：
--
作者：
Giudicessi, John R.;Ye, Dan;Tester, David J.;Crotti, Lia;Mugione, Alessandra;Nesterenko, Vladislav V.;Albertson, Richard M.;Antzelevitch, Charles;Schwartz, Peter J.;Ackerman, Michael J.
关键词：
Brugada综合征（BrS）是一种猝死易感性遗传病，心电图表现为V1-V3导联st段抬高。鉴于瞬时外向电流（Ito）在BrS发病机制中的重要作用，我们假设KCND3中罕见的功能获得突变可能是BrS的致病底物。采用PCR、DHPLC和直接测序技术对86例BrS1-8基因型阴性BrS患者的kcnd3编码的Kv4.3 （Ito）进行了全面的突变分析。研究人员检查了780名健康个体的DNA，以评估非同义变异的等位基因频率。假设的brs相关Kv4.3突变在HEK293细胞中被工程化并与野生型KChIP2共表达。用全细胞膜片钳记录野生型和突变型Ito离子电流。2例BrS1-8基因型阴性病例具有新的Kv4.3错义突变。Kv4.3-L450F和Kv4.3-G600R在1560个参考等位基因中均缺失，所涉及的残基在物种间高度保守。Kv4.3-L450F和Kv4.3-G600R均表现出功能获得型表型，峰值Ito电流密度分别提高了146.2% （n=15, p<0.05）和50.4% （n=15, p<0.05）。采用Luo-Rudy II AP模型的模拟表明，由于L450F或G600R的杂合表达增加了Ito最大电导，导致AP圆顶的稳定损失。这些发现提供了第一个分子和功能证据，表明新的KCND3功能获得突变在BrS的发病机制和表型表达中起作用，在KCND3表达最高的右心室，遗传增强的Ito电流梯度可能导致致命性心律失常。
Brugada syndrome (BrS) is a sudden death predisposing genetic condition characterized electrocardiographically by ST-segment elevation in the leads V1-V3. Given the prominent role of the transient outward current (Ito) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Comprehensive mutational analysis of KCND3-encoded Kv4.3 (Ito) was conducted using PCR, DHPLC, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for non-synonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and co-expressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant Ito ion currents were recorded using whole cell patch clamp. Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak Ito current density by 146.2% (n=15, p<0.05) and 50.4% (n=15, p<0.05) respectively. Simulations employing a Luo-Rudy II AP model demonstrated the stable loss of the AP dome as a result of the increased Ito maximal conductance associated with the heterozygous expression of either L450F or G600R. These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced Ito current gradient within the right ventricle were KCND3 expression is the highest.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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