Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation.
Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation.
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DOI：
10.1016/j.hrthm.2009.04.015
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发表时间：
2009-08
期刊：
影响因子：
5.5
通讯作者：
Ellinor, Patrick T.
中科院分区：
文献类型：
--
作者：
Das, Saumya;Makino, Seiko;Melman, Yonathan F.;Shea, Marisa A.;Goyal, Sanjeev B.;Rosenzweig, Anthony;MacRae, Calum A.;Ellinor, Patrick T.
据报道，几种离子通道基因的突变会导致罕见的家族性房颤（AF）病例。我们试图确定一个常染色体显性遗传性房颤家族的遗传基础。通过12导联心电图、超声心动图、信号平均P波分析和实验室研究对家族成员进行评估。研究了AF-324中的14个家族成员。6名患者患有房颤，平均发病年龄为32岁（范围16-59岁）。与未受影响的家族成员相比，AF患者的平均QRS时限较长（100 vs. 86 ms（p= 0. 015）），但校正QT间期无差异（423 ± 15 ms vs. 421 ± 21 ms）。对已知的AF和其他心血管疾病的基因座进行了评估;利用位于KCNQ 1内的标记D11 S4088获得了连锁的证据，发现第三跨膜区中高度保守的丝氨酸突变为脯氨酸（S209 P）。与野生型通道相比，S209 P突变体激活更快，失活更慢，并且在电压激活曲线中具有超极化偏移。一部分突变通道在所有电压下组成性开放，导致IKs电流净增加。我们已经确定了一个家庭与孤立的AF由于突变的高度保守的S3结构域KCNQ 1，一个区域的通道以前没有牵连的发病机制AF。
Mutations in several ion channel genes have been reported to cause rare cases of familial atrial fibrillation (AF). We sought to determine the genetic basis for AF in a family with autosomal dominant AF. Family members were evaluated by 12-lead ECG, echocardiogram, signal averaged P wave analysis, and laboratory studies. Fourteen family members in AF-324 were studied. Six individuals had AF with a mean age at onset of 32 years (range 16–59). Compared to unaffected family members, those with AF had a longer mean QRS duration (100 vs. 86 ms (p=0.015), but no difference in the corrected QT interval (423 ± 15 ms vs. 421 ± 21 ms). The known loci for AF and other cardiovascular diseases were evaluated; evidence of linkage was obtained with marker D11S4088 located within KCNQ1, and a highly conserved serine in the third transmembrane region was found to be mutated to a proline (S209P). Compared to the wild type channel, the S209P mutant activates more rapidly, deactivates more slowly, and has a hyperpolarizing shift in the voltage activation curve. A fraction of the mutant channels are constitutively open at all voltages resulting in a net increase in the IKs current. We have identified a family with lone AF due to a mutation in the highly conserved S3 domain of KCNQ1, a region of the channel not previously implicated in the pathogenesis of AF.
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影响因子：
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