A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity
A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity
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罕见的 KIF1A 错义突变增强突触功能并增加癫痫发作活动
DOI：
10.3389/fgene.2020.00061
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发表时间：
2020-02-27
影响因子：
3.7
通讯作者：
Tian, Xin
中科院分区：
文献类型：
--
作者：
Guo, Yi;Chen, Yuanyuan;Tian, Xin
虽然遗传因素被认为是癫痫的主要病因，但大多数癫痫患者的遗传性癫痫的原因仍然未知。驱动蛋白家族成员1A（Kinesin family member 1A，KIF 1A）是一种神经元特异性的运动蛋白，其与微管一起沿着运动，负责膜性细胞器和突触小泡的运输。KIF1A的变体最近与遗传性痉挛性截瘫（HSP），遗传性感觉和自主神经病变2型（HSANII）和智力残疾有关。然而，KIF1A突变尚未在癫痫患者中检测到。在我们的研究中，我们对一个家族的癫痫相关基因进行了定制测序，该家族有六名三代以上的全身性癫痫患者，并在KIF1A中发现了一个罕见的杂合突变（c.1190C > A，p.Ala397Asp）。原代培养神经元的全细胞记录显示，突变KIF1A增加了兴奋性突触传递，但没有增加神经元的内在兴奋性，斑马鱼的表型测试表明，这种罕见的突变导致癫痫样活动。这些结果提供了新的证据，表明KIF1A功能障碍参与癫痫发生。
Although genetic factors are considered a main etiology of epilepsy, the causes of genetic epilepsy in the majority of epilepsy patients remain unknown. Kinesin family member 1A (KIF1A), a neuron-specific motor protein that moves along with microtubules, is responsible for the transport of membranous organelles and synaptic vesicles. Variants of KIF1A have recently been associated with hereditary spastic paraplegia (HSP), hereditary sensory and autonomic neuropathy type 2 (HSANII), and intellectual disability. However, mutations in KIF1A have not been detected in patients with epilepsy. In our study, we conducted customized sequencing of epilepsy-related genes of a family with six patients with generalized epilepsy over three generations and identified a rare heterozygous mutation (c.1190C > A, p. Ala397Asp) in KIF1A. Whole-cell recordings from primary cultured neurons revealed that the mutant KIF1A increases the excitatory synaptic transmission but not the intrinsic excitability of neurons, and phenotype testing in zebrafish showed that this rare mutation results in epileptic seizure-like activity. These results provide new evidence demonstrating that KIF1A dysfunction is involved in epileptogenesis.