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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy.
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Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy.

机译：起搏器HCN2通道中的隐性功能丧失突变导致特发性全身性癫痫患者神经元兴奋性增加。

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摘要

The hyperpolarization-activated I(h) current, coded for by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, controls synaptic integration and intrinsic excitability in many brain areas. Because of their role in pacemaker function, defective HCN channels are natural candidates for contributing to epileptogenesis. Indeed, I(h) is pathologically altered after experimentally induced seizures, and several independent data indicate a link between dysfunctional HCN channels and different forms of epilepsy. However, direct evidence for functional changes of defective HCN channels correlating with the disease in human patients is still elusive. By screening families with epilepsy for mutations in Hcn1 and Hcn2 genes, we found a recessive loss-of-function point mutation in the gene coding for the HCN2 channel in a patient with sporadic idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the mutation. The mutation (E515K) is located in the C-linker, a region known to affect channel gating. Functional analysis revealed that homomeric mutant, but not heteromeric wild-type/mutant channels, have a strongly inhibited function caused by a large negative shift of activation range and slowed activation kinetics, effectively abolishing the HCN2 contribution to activity. After transfection into acutely isolated newborn rat cortical neurons, homomeric mutant, but not heteromeric wild type/mutant channels, lowered the threshold of action potential firing and strongly increased cell excitability and firing frequency when compared with wild-type channels. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.
机译：由超极化激活的环状核苷酸门控（HCN）通道编码的超极化激活的I（h）电流可控制许多大脑区域的突触整合和内在兴奋性。由于HCN通道在起搏器功能中的作用，因此它们是促成癫痫发生的自然候选者。实际上，实验诱发的癫痫发作后I（h）在病理上发生了改变，并且一些独立的数据表明功能异常的HCN通道与癫痫的不同形式之间存在联系。然而，人类患者中与疾病相关的有缺陷的HCN通道功能改变的直接证据仍然难以捉摸。通过筛查患有癫痫的家庭中Hcn1和Hcn2基因的突变，我们发现患有散发性特发性全身性癫痫的患者中，编码HCN2通道的基因中存在隐性功能丧失点突变。在同一个家族的17个筛查成员中，先证者是唯一受到影响且是纯合突变的人。突变（E515K）位于C连接子中，该区域已知会影响通道门控。功能分析表明，同源突变体，而不是异源野生型/突变体通道，具有强烈的抑制功能，这是由于激活范围的较大负移和减慢的激活动力学所致，从而有效地消除了HCN2对活性的贡献。与野生型通道相比，转染入急性分离的新生大鼠皮层神经元后，同型突变体而非异源野生型/突变体通道降低了动作电位激发的阈值，并大大提高了细胞兴奋性和激发频率。这是人类首次发现HCN2的单点纯合功能丧失突变，可能与具有隐性遗传的广泛性癫痫有关。

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