A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability.
A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability.
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DOI：
10.3389/fnmol.2018.00269
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发表时间：
2018
影响因子：
4.8
通讯作者：
DiFrancesco D
中科院分区：
文献类型：
--
作者：
Campostrini G;DiFrancesco JC;Castellotti B;Milanesi R;Gnecchi-Ruscone T;Bonzanni M;Bucchi A;Baruscotti M;Ferrarese C;Franceschetti S;Canafoglia L;Ragona F;Freri E;Labate A;Gambardella A;Costa C;Gellera C;Granata T;Barbuti A;DiFrancesco D
HCN通道在神经元中高度表达且功能相关，越来越多的证据表明其参与人类癫痫的病因学。在HCN亚型中，HCN 4在心脏组织中很重要，它是心脏起搏器活动的基础。尽管在大脑的深层结构中也有表达，但尚未报道该通道的突变在功能上与癫痫相关。我们使用下一代测序技术筛查特发性癫痫患者，在两个患有婴儿良性肌阵挛性癫痫的兄弟中发现了HCN 4上的p.Arg550Cys（c.1648C>T）杂合突变。异源表达系统和神经元中的功能表征表明，突变决定了HCN 4对活性的贡献的功能丧失和神经元放电的增加，可能诱发癫痫。在心肌细胞中表达，突变型通道在比野生型（WT）略多的负电压下激活，与临界心动过缓一致。虽然HCN 4变体经常与心律失常相关，但这些数据代表了HCN 4的功能改变也可以通过功能丧失效应和相关的神经元兴奋性增加参与人类癫痫的第一个实验证据。由于HCN 4似乎只在发育早期在脑深部结构中高度表达，我们的数据为功能障碍的HCN 4和婴儿癫痫之间的联系提供了一个潜在的解释。这些研究结果表明，它可能是有用的，包括HCN4筛选，以扩大知识的遗传原因的婴儿癫痫，可能铺平了道路，为识别创新的治疗策略。
HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies.
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影响因子：
3.3
作者：
Bender, RA;Brewster, A;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
11.2
作者：
Arsov, Todor;Mullen, Saul A.;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.
影响因子：
2.3
作者：
DiFrancesco, Jacopo C.;Sestini, Roberta;Ferrarese, Carlo
通讯作者：
Ferrarese, Carlo
影响因子：
64.8
作者：
BROWN, HF;DIFRANCESCO, D;NOBLE, SJ
通讯作者：
NOBLE, SJ
DOI：
10.1073/pnas.1010122108
发表时间：
2011-01-25
影响因子：
11.1
作者：
Baruscotti, Mirko;Bucchi, Annalisa;DiFrancesco, Dario
通讯作者：
DiFrancesco, Dario