Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8.
Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8.
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DOI：
10.1016/j.hrthm.2011.10.035
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发表时间：
2012-04
期刊：
影响因子：
5.5
通讯作者：
Antzelevitch, Charles
中科院分区：
文献类型：
--
作者：
Barajas-Martinez, Hector;Hu, Dan;Ferrer, Tania;Onetti, Carlos G.;Wu, Yuesheng;Burashnikov, Elena;Boyle, Madalene;Surman, Tyler;Urrutia, Janire;Veltmann, Christian;Schimpf, Rainer;Borggrefe, Martin;Wolpert, Christian;Ibrahim, Bassiema B.;Antonio Sanchez-Chapula, Jose;Winters, Stephen;Haissaguerre, Michel;Antzelevitch, Charles
关键词：
atp敏感钾（KATP）心脏通道由向内整流通道亚基Kir6.1或Kir6.2（由KCNJ8或KCNJ11编码）和磺酰脲受体亚基SUR2A（由ABCC9编码）组成。目的探讨KCNJ8基因突变与Brugada （BrS）和早期复极化（ERS）综合征的关系，并阐明KATP通道电流（IK-ATP）功能增强的机制。对204个BrS和ERS先证及家族成员进行了KCNJ8等候选基因的直接测序。采用全细胞法和内外膜片钳法研究TSA201细胞中表达的突变通道。KCNJ8中相同的错义突变p.Ser422Leu （c.1265C>T）在3个BrS和1个ERS先证中被发现，但在种族匹配的健康对照的430个等位基因中不存在。其他遗传变异包括CACNB2b-D601E。全细胞膜片钳研究表明，当KCNJ8-S422L与sur2a野生型共表达时，格列本脲敏感IK-ATP的功能增加了两倍。内外膜片钳评估显示突变通道中ATP的IC50显著增加（785.5±2比38.4±3µM, n=5; p<0.01），表明在常温条件下KATP通道不完全关闭。具有CACNB2b-D601E多态性的患者表现出较长的QT/QTc间隔，可能是由于其诱导ICa-L增加的作用。我们的研究结果支持KCNJ8是Brugada和早期复极综合征的易感基因的假设，并指出S422L可能是热点突变。我们的研究结果表明，s422l诱导的IK-ATP功能的增强是由于对细胞内ATP的敏感性降低。
ATP-sensitive potassium (KATP) cardiac channels consist of inward rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9). To examine the association of mutations in KCNJ8 with Brugada (BrS) and early repolarization (ERS) syndromes and elucidate the mechanism underlying the gain of function of KATP channel current (IK-ATP). Direct sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch clamp methods were used to study mutated channels expressed in TSA201 cells. The same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS proband, but was absent in 430 alleles from ethnically-matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole cell patch clamp studies showed a two-fold gain of function of glibenclamide-sensitive IK-ATP when KCNJ8-S422L was co-expressed with SUR2A-wild type. Inside-out patch clamp evaluation yielded a significantly greater IC50 for ATP in the mutant channels (785.5±2 vs. 38.4±3 µM, n=5; p<0.01) pointing to incomplete closing of the KATP channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/QTc intervals, likely due to their effect to induce an increase in ICa-L. Our results support the hypothesis that KCNJ8 is a susceptibility gene for Brugada and early repolarization syndromes and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in IK-ATP is due to reduced sensitivity to intracellular ATP.
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影响因子：
5.5
作者：
Burashnikov, Elena;Pfeiffer, Ryan;Barajas-Martinez, Hector;Delpon, Eva;Hu, Dan;Desai, Mayurika;Borggrefe, Martin;Haeissaguerre, Michel;Kanter, Ronald;Pollevick, Guido D.;Guerchicoff, Alejandra;Laino, Ruben;Marieb, Mark;Nademanee, Koonlawee;Nam, Gi-Byoung;Robles, Roberto;Schimpf, Rainer;Stapleton, Dwight D.;Viskin, Sami;Winters, Stephen;Wolpert, Christian;Zimmern, Samuel;Veltmann, Christian;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
DOI：
10.1152/ajpheart.1996.271.2.h548
发表时间：
1996-08-01
影响因子：
4.8
作者：
DiDiego, JM;Sun, ZQ;Antzelevitch, C
通讯作者：
Antzelevitch, C
影响因子：
1.3
作者：
Gussak, I;Antzelevitch, C
通讯作者：
Antzelevitch, C
影响因子：
--
作者：
Morrissey, Alison;Rosner, Erika;Coetzee, William A
通讯作者：
Coetzee, William A
影响因子：
4.5
作者：
NOMA, A;MORAD, M;IRISAWA, H
通讯作者：
IRISAWA, H