A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.
A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.
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DOI：
10.1371/journal.pone.0106982
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Pitt GS
中科院分区：
文献类型：
--
作者：
Hennessey JA;Boczek NJ;Jiang YH;Miller JD;Patrick W;Pfeiffer R;Sutphin BS;Tester DJ;Barajas-Martinez H;Ackerman MJ;Antzelevitch C;Kanter R;Pitt GS
CACNA1C基因突变增加了通过CaV1.2 L型钙通道的电流，是罕见的长QT综合征(LQTS)和Timothy综合征(TS)的基础。我们通过候选基因测序在一名患有心律失常和心外特征的菲律宾裔男性儿童中发现了CACNA1C的一个变异，并进行了功能表达研究，以确定该变异对CaV1.2通道的影响。在婴儿时期，受试者在30个月大时出现癫痫发作并表现出发育迟缓。5岁时QT间期为520ms，室性心动过速复发。17岁时体检以小头畸形、身材矮小、肢体无力和萎缩伴反射亢进、痉挛双瘫、多发性龋齿和横纹肌溶解为特征。候选基因测序发现了CACNA1C(Rs374528680)5731位的G>；C颠换，预测了CaV1.2的1911位(p.G1911R)的甘氨酸和精氨酸替换。该变异的等位基因频率在马来人为0.01，但在984个高加索人等位基因和1000个基因组计划中缺失。在电生理分析中，该变异体减少了电压依赖的失活，从而导致CaV1.2功能的增强。我们还观察到激活的V1/2负移和通道失活的V1/2正移，导致窗口电流增加。总之，这些提示了CaV1.2的功能获得效应，并提示在某些临床环境下心律失常的易感性增加。在一例原因不明的婴儿猝死(SUID)中也发现了p.G1911R突变，越来越多的临床观察表明这种突变可能与心脏离子通道的致心律失常突变有关。综上所述，CACNA1C变异体减少CaV1.2的电压依赖性失活和增加窗口电流的综合作用扩大了我们对CaV1.2功能增强有助于QT延长的机制的理解。
Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of CaV1.2 can contribute to QT prolongation.
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影响因子：
8.8
作者：
Dittmer PJ;Dell'Acqua ML;Sather WA
通讯作者：
Sather WA
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
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：
5.5
作者：
Van Norstrand, David W.;Tester, David J.;Ackerman, Michael J.
通讯作者：
Ackerman, Michael J.
影响因子：
4.6
作者：
Cohen-Kutner, Moshe;Yahalom, Yfat;Trus, Michael;Atlas, Daphne
通讯作者：
Atlas, Daphne