Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy
Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy
复制标题
GABRG2 的罕见变异与睡眠相关的过度运动性癫痫有关
DOI：
10.1007/s00415-022-11137-4
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发表时间：
2022
影响因子：
6
通讯作者：
Wen Jiang
中科院分区：
文献类型：
--
作者：
Yong;Changgeng Song;Huiyuan Zhou;B. Feng;Jing;Yu Liu;Yulin Man;Jing Han;Shui;Wen Jiang
睡眠相关性高运动性癫痫（Sleep-related hypermotor epilepsy，SHE）是一种局灶性癫痫综合征。其病理生理机制与γ-氨基丁酸A型受体（γ-aminobutyric acid type A receptor，GABAAR）介导的GABA能神经传递功能紊乱密切相关。因此，我们有理由认为罕见的GABAAR变异可能与SHE的发病机制有关。为了验证这一假设，我们在58名SHE患者中进行了下一代测序，并使用电生理记录、蛋白质印迹、流式细胞术和共聚焦显微镜的组合分析了所鉴定的变体在神经元和非神经元细胞中的功能效应。在我们的研究中，我们在三名无关患者中检测到GABRG 2（MIM：137，164，编码GABAAR γ2亚基）中的三种罕见变异（NM_198904.2：c.269C> T，p.T90M; NM_198904.2：c.950C > A，p.T317N和NM_198903.2：c.649C > T，p.Q217X）。三种罕见变异中有两种通过母体（T90 M）或父亲（Q217 X）传播，而T317 N变异是新发的。携带T90 M变异的先证者的母亲未受影响，并且为该变异的嵌合体。功能分析表明，T90 M和T317 N变体通过多种机制降低GABA诱发的电流幅度，包括受损的表面表达、内质网滞留和通道门控缺陷。Q217 X变异体减少了GABAAR的突触聚集和分布。虽然不能直接从这些结果中确定这些变体的因果作用，但功能评估和基因测序表明，这些罕见的GABRG 2变体可能构成SHE的遗传风险因素。我们的研究进一步扩展了GABRG 2表型谱，并支持GABA能神经传递参与SHE癫痫发生的观点。
Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome. The underlying pathophysiology is presumed to be closely related with disruption of GABAergic neurotransmission, which is mainly medicated by γ-aminobutyric acid type A receptor (GABAAR). Thus, it is reasonable to assume that rare GABAAR variants might contribute to the pathogenesis of SHE. To test this hypothesis, we performed next-generation sequencing in 58 SHE patients and analyzed the functional effects of the identified variants in both neuronal and non-neuronal cells using a combination of electrophysiology recordings, western blot, flow cytometry, and confocal microscopy. In our study, we detected three rare variants (NM_198904.2: c.269C > T, p.T90M; NM_198904.2: c.950C > A, p.T317N and NM_198903.2: c.649C > T, p.Q217X) in GABRG2 (MIM:137,164, encoding GABAAR γ2 subunit) in three unrelated patients. Two of the three rare variants were transmitted unaffected maternally (T90M) or unaffected paternally (Q217X), whereas the T317N variant arose de novo. The mother of proband carrying the T90M variant was unaffected and being mosaicism for this variant. Functional analysis showed that T90M and T317N variants decreased GABA-evoked current amplitudes by diverse mechanisms including impaired surface expression, endoplasmic reticulum retention, and channel gating defects. And Q217X variant reduced synaptic clustering and distribution of GABAAR. While a causal role of these variants cannot be established directly from these results, the functional assessment together with the genetic sequencing suggests that these rare GABRG2 variants may constitute genetic risk factors for SHE. Our study further expands the GABRG2 phenotypic spectrum and supports the view that GABAergic neurotransmission participates in the epileptogenesis of SHE.
影响因子：
3.5
作者：
Warner, Timothy A.;Shen, Wangzhen;Kang, Jing-Qiong
通讯作者：
Kang, Jing-Qiong
影响因子：
13.6
作者：
Kang JQ;Macdonald RL
通讯作者：
Macdonald RL
影响因子：
29
作者：
Kang JQ;Macdonald RL
通讯作者：
Macdonald RL