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Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy

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Abstract

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.

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Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We gratefully acknowledge Dr. Yang Ying for making critical comments for interpretation of the genetic variants identified. We thank Drs. Xiaoli Wang, Lang Jin, and Beibei Chen for technical assistance. We also thank the patients for their participation in this study.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No.81974204).

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Author notes

  1. Jing Han, Shui-bing Liu and Wen Jiang have contributed equally to this work.

Authors and Affiliations

  1. Comprehensive Epilepsy Center, Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Yong-li Jiang, Chang-geng Song, Hui-min Zhou, Jing-jing Zhao, Yu Liu, Yu-lin Man & Wen Jiang

  2. Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, China

    Ban Feng & Shui-bing Liu

  3. MOE Key Laboratory of Modern Teaching Technology, Center for Teacher Professional Ability Development, Shaanxi Normal University, 199 South Chang’an Road, Xi’an, China

    Jing Han

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  1. Yong-li Jiang
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Contributions

YJ: Conceptualization, writing-original draft preparation, methodology, formal analysis, visualization. CS, HZ, and BF: Investigation, methodology, formal analysis, visualization. JZ, YL, and YM: Methodology, formal analysis, visualization. JH, SL: Conceptualization, writing-reviewing and editing, visualization, supervision. WJ: Conceptualization, writing-reviewing and editing, visualization, supervision, funding acquisition.

Corresponding authors

Correspondence to Jing Han, Shui-bing Liu or Wen Jiang.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was approved by the Ethics Committee of Xijing Hospital and conducted in agreement with the relevant guidelines and regulations.

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Written informed consent was obtained from the patients and their parents/legal guardians.

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Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

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Jiang, Yl., Song, Cg., Zhou, Hm. et al. Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy. J Neurol 269, 4939–4954 (2022). https://doi.org/10.1007/s00415-022-11137-4

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