FGF12 is a candidate Brugada syndrome locus.
FGF12 is a candidate Brugada syndrome locus.
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FGF12 是 Brugada 综合征的候选基因座。
DOI：
10.1016/j.hrthm.2013.09.064
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发表时间：
2013-12
期刊：
影响因子：
5.5
通讯作者：
Pitt, Geoffrey S.
中科院分区：
文献类型：
--
作者：
Hennessey, Jessica A.;Marcou, Cherisse A.;Wang, Chuan;Wei, Eric Q.;Wang, Chaojian;Tester, David J.;Torchio, Margherita;Dagradi, Federica;Crotti, Lia;Schwartz, Peter J.;Ackerman, Michael J.;Pitt, Geoffrey S.
不到30%的Brugada综合征（BrS）病例有明确的遗传原因。在已知的BrS易感基因中，SCN 5A或CACNA 1C及其辅助亚基的功能丧失突变是最常见的。最近的研究表明，成纤维细胞生长因子（FGF）同源因子（FHFs; FGF 11-FGF 14）调节心脏Na+和Ca 2+通道电流的基础上，我们假设FHFs是候选的BrS位点。本研究的目的是测试FGF 12是否是一个候选的BrS位点。我们使用定量聚合酶链反应，以确定主要的FHF表达在人类心室，然后查询表型阳性，基因型阴性的BrS生物储存与BrS相关的FHF突变。我们质疑的影响，一个确定的突变与生化分析结合电生理评估在一个新的大鼠心室心肌细胞系统，在该系统中，我们交换了内源性FHF与确定的突变体上的多个离子电流在其自然环境和心脏动作电位。我们鉴定FGF 12为在人心室中表达的主要FHF。在生物库的102个个体中，我们鉴定了FGF 12-B（Q7 R-FGF 12）中的单个错义突变。该突变体减少了与NaV1.5 C末端的结合，但不减少与介导Ca 2+通道调节的亲连接蛋白-2的结合。在大鼠中，成年心肌细胞Q7 R-FGF 12，而不是野生型FGF 12，降低Na+通道电流密度和可用性，而不影响Ca 2+通道功能。此外，突变体，而不是野生型FGF 12，降低动作电位振幅，这是一致的Mud诱导的Na+通道功能的丧失。这些多层次的研究强烈表明，Q7 R-FGF 12是一种疾病相关的BrS突变。此外，这些数据首次表明FHF对Na+和Ca 2+通道的影响是可分离的。最重要的是，这项研究建立了一种新的方法来分析人类致突变基因对心脏离子电流的影响。
Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11–FGF14) regulate cardiac Na+ and Ca2+ channel currents, we hypothesized that FHFs are candidate BrS loci. The goal of this study was to test whether FGF12 is a candidate BrS locus. We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment in a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant on multiple ionic currents in their native milieu and on the cardiac action potential. We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2, which mediates Ca2+ channel regulation. In rats, adult cardiac myocytes Q7R-FGF12, but not wild-type FGF12, reduced Na+ channel current density and availability without affecting Ca2+ channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na+ channel function. These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na+ and Ca2+ channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.
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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：
10.1161/circgenetics.113.000138
发表时间：
2013-06
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Boczek NJ;Best JM;Tester DJ;Giudicessi JR;Middha S;Evans JM;Kamp TJ;Ackerman MJ
通讯作者：
Ackerman MJ
影响因子：
5.3
作者：
Laezza, Fernanda;Gerber, Benjamin R.;Nerbonne, Jeanne M.
通讯作者：
Nerbonne, Jeanne M.
影响因子：
20.1
作者：
Hennessey JA;Wei EQ;Pitt GS
通讯作者：
Pitt GS
影响因子：
20.1
作者：
Wang C;Hennessey JA;Kirkton RD;Wang C;Graham V;Puranam RS;Rosenberg PB;Bursac N;Pitt GS
通讯作者：
Pitt GS