Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy

被引:9
|
作者
Jiang, Yong-Li [1 ]
Song, Chang-Geng [1 ]
Zhou, Hui-Min [1 ]
Feng, Ban [2 ]
Zhao, Jing-Jing [1 ]
Liu, Yu [1 ]
Man, Yu-Lin [1 ]
Han, Jing [3 ]
Liu, Shui-Bing [2 ]
Jiang, Wen [1 ]
机构
[1] Fourth Mil Med Univ, Xijing Hosp, Comprehens Epilepsy Ctr, Dept Neurol, Xian 710032, Peoples R China
[2] Fourth Mil Med Univ, Sch Pharm, Dept Pharmacol, Xian, Peoples R China
[3] Shaanxi Normal Univ, Ctr Teacher Profess Abil Dev, MOE Key Lab Modern Teaching Technol, 199 South Changan Rd, Xian 710032, Peoples R China
基金
中国国家自然科学基金;
关键词
Sleep-related hypermotor epilepsy; GABA(A) receptor; GABRG2; Next-generation sequencing; FRONTAL-LOBE EPILEPSY; MOUSE MODELS; MUTATION; SUBUNIT; MUTANT; BIOGENESIS;
D O I
10.1007/s00415-022-11137-4
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 gamma-aminobutyric acid type A receptor (GABA(A)R). Thus, it is reasonable to assume that rare GABA(A)R 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 GABA(A)R gamma(2) 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 GABA(A)R. 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.
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收藏
页码:4939 / 4954
页数:16
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