An epileptic encephalopathy associated<i>GABRG2</i>missense mutation leads to pre- and postsynaptic defects in zebrafish

Zhou, Jing; Liang, Wenpeng; Wang, Jie; Chen, Juan; Liu, Dong; Wang, Xin; Wu, Youjia; Zhang, Qi; Shen, Dingding

doi:10.1093/hmg/ddab338

Cited by 7 publications

(9 citation statements)

References 59 publications

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“…Preclinical studies showed that zebrafish overexpressing mutant human GABRG2 (p.(Phe343Leu)) subunits mimicked the human DEE phenotype. 29,30 Moreover, gabrg2 −/− zebrafish mutants are prone to light-induced seizures and respond well to VPA 31 ; mimicking the phenotype and drug response of our patient.…”

Section: Discussionsupporting

confidence: 64%

“…Most Sunflower syndrome patients have difficult to treat epilepsy, which could also be the case for our patient although longer follow‐up is needed to confirm this constellation. Preclinical studies showed that zebrafish overexpressing mutant human GABRG2 (p.(Phe343Leu)) subunits mimicked the human DEE phenotype 29,30 . Moreover, gabrg2 −/− zebrafish mutants are prone to light‐induced seizures and respond well to VPA 31 ; mimicking the phenotype and drug response of our patient.…”

Section: Discussionsupporting

confidence: 52%

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A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring

Sourbron,

Proost,

Jansen

et al. 2023

Epileptic Disorders

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ObjectiveSunflower syndrome is a unique photosensitive epilepsy, characterized by heliotropism and stereotyped seizures associated with handwaving. These handwaving events (HWE) are thought to be an ictal phenomenon, although current data are contrasting. Photosensitive epilepsy occurs in 2‐5% of the epilepsy forms and several pathogenic gene variants have been associated with photosensitive epilepsy. However, the genetic etiology of Sunflower syndrome remains unknown. Antiseizure medications (ASM) efficacious in treating photosensitive epilepsy are valproic acid (VPA) and levetiracetam (LEV) although some forms, such as Sunflower syndrome, can be drug‐resistant.ResultsHere, we report an 8‐year‐old boy with an early onset of episodes of HWE that was initially categorized as behavioral problems for which risperidone was started. However, the medical history was suggestive of Sunflower syndrome and subsequent video EEG showed focal mostly temporal and fronto‐temporal (right and left) epileptiform activity and confirmed the epileptic nature of the HWE. Thus, VPA was started and initially led to seizure frequency reduction. Molecular analyses showed a pathogenic variant in GABRG2 (c.1287G>A p.(Trp429Ter)), which has been associated with photosensitive and generalized epilepsy.SignificanceOverall, clinicians worldwide should be cautious by interpreting HWE and/or other tic‐like movements, since an epileptic origin cannot be ruled out. A prompt and correct diagnosis can be made by performing a video EEG early on in the diagnostic process when epileptic seizures are part of the differential diagnosis. Even though the genetic etiology of Sunflower syndrome remains poorly understood, this constellation supports further genetic testing since the detection of a pathogenic variant can help in making correct decisions regarding ASM management.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionsupporting

confidence: 52%

A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring

Sourbron,

Proost,

Jansen

et al. 2023

Epileptic Disorders

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“…To detect the effect of locations of mutations on phenotypes, we compared the locomotive activity of different mutant GABRG2 transgenic zebrafish. In the previous research, we generated F343L and I107T transgenic zebrafish with spontaneous seizures 6,10 . In this research, the distance traveled in 30 min at 5 dpf was compared in the above three transgenic lines and the data showed that all mutant zebrafish traveled more than the WT control group, showing an epileptic phenotype.…”

Section: Resultsmentioning

confidence: 93%

“…In the previous research, we generated F343L and I107T transgenic zebrafish with spontaneous seizures. 6,10 In this research, the distance traveled in 30 min at 5 dpf was compared in the above three transgenic lines and the data showed that all mutant zebrafish traveled more than the WT control group, showing an epileptic phenotype. Among the three mutant zebrafish models, the I107T line traveled the most while the P282S line traveled the least, and the difference between the two groups was significant (1774 ± 94.55 mm in the I107T group vs. 1125 ± 106.9 mm in the P282S group, p = 0.0010, Figure 4A), indicating a less active phenotype induced by P282S mutation.…”

Section: Comparison Of Different Mutant Gabrg2 Transgenic Zebrafish M...mentioning

confidence: 87%

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations

Sui,

Zhan,

et al. 2024

CNS Neurosci Ther

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ObjectiveTo explore the mechanism involved in variable phenotypes of epilepsy models induced by γ‐aminobutyric acid type A γ2 subunit (GABRG2) mutations.MethodsThe zebrafish carrying wild‐type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video‐Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio‐signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations.ResultsThe established Tg(hGABRG2P282S) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2P282S) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2P282S) zebrafish. In addition, the behavioral activity, production of pro‐inflammatory factors, and activation of the IL‐2 receptor signal pathway varied among the three mutant zebrafish lines.ConclusionWe successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.

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“…RNA-sequencing analysis of mutation of GABRA1 in zebrafish larval brains identified a marked downregulation of genes encoding inhibitory synaptic components as well as proteins involved in axon guidance. Immunocytochemical analysis revealed a marked decrease in the accumulation of GABA synaptic markers; consistently, transgene GABRG2 mutation resulted in postsynaptic and presynaptic defects ( 64 , 65 ). GABRG2 was found to be associated with suicidal behavior and major depressive disorder ( 66 ).…”

Section: Discussionmentioning

confidence: 91%

Identification of key genes and signaling pathways associated with dementia with Lewy bodies and Parkinson's disease dementia using bioinformatics

Sun

et al. 2023

Front. Neurol.

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ObjectiveDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are collectively known as Lewy body dementia (LBD). Considering the heterogeneous nature of LBD and the different constellations of symptoms with which patients can present, the exact molecular mechanism underlying the differences between these two isoforms is still unknown. Therefore, this study aimed to explore the biomarkers and potential mechanisms that distinguish between PDD and DLB.MethodsThe mRNA expression profile dataset of GSE150696 was acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between 12 DLB and 12 PDD were identified from Brodmann area 9 of human postmortem brains using GEO2R. A series of bioinformatics methods were applied to identify the potential signaling pathways involved, and a protein–protein interaction (PPI) network was constructed. Weighted gene co-expression network analysis (WGCNA) was used to further investigate the relationship between gene co-expression and different LBD subtypes. Hub genes that are strongly associated with PDD and DLB were obtained from the intersection of DEGs and selected modules by WGCNA.ResultsA total of 1,864 DEGs between PDD and DLB were filtered by the online analysis tool GEO2R. We found that the most significant GO- and KEGG-enriched terms are involved in the establishment of the vesicle localization and pathways of neurodegeneration-multiple diseases. Glycerolipid metabolism and viral myocarditis were enriched in the PDD group. A B-cell receptor signaling pathway and one carbon pool by folate correlated with DLB in the results obtained from the GSEA. We found several clusters of co-expressed genes which we designated by colors in our WGCNA analysis. Furthermore, we identified seven upregulated genes, namely, SNAP25, GRIN2A, GABRG2, GABRA1, GRIA1, SLC17A6, and SYN1, which are significantly correlated with PDD.ConclusionThe seven hub genes and the signaling pathways we identified may be involved in the heterogeneous pathogenesis of PDD and DLB.

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An epileptic encephalopathy associatedGABRG2missense mutation leads to pre- and postsynaptic defects in zebrafish

Cited by 7 publications

References 59 publications

A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring

A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations

Identification of key genes and signaling pathways associated with dementia with Lewy bodies and Parkinson's disease dementia using bioinformatics

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