PUBLICATION
An epileptic encephalopathy associated GABRG2 missense mutation leads to pre- and postsynaptic defects in zebrafish
- Authors
- Zhou, J., Liang, W., Wang, J., Chen, J., Liu, D., Wang, X., Wu, Y., Zhang, Q., Shen, D.
- ID
- ZDB-PUB-211230-39
- Date
- 2021
- Source
- Human molecular genetics 31(19): 3216-3230 (Journal)
- Registered Authors
- Liu, Dong
- Keywords
- none
- MeSH Terms
-
- Animals
- Brain Diseases*
- Humans
- Mutation
- Mutation, Missense/genetics
- Receptors, GABA-A*/genetics
- Receptors, GABA-A*/metabolism
- Seizures
- Zebrafish/genetics
- Zebrafish/metabolism
- gamma-Aminobutyric Acid/genetics
- PubMed
- 34957497 Full text @ Hum. Mol. Genet.
Citation
Zhou, J., Liang, W., Wang, J., Chen, J., Liu, D., Wang, X., Wu, Y., Zhang, Q., Shen, D. (2021) An epileptic encephalopathy associated GABRG2 missense mutation leads to pre- and postsynaptic defects in zebrafish. Human molecular genetics. 31(19):3216-3230.
Abstract
Mutations in the γ-aminobutyric acid type A (GABAA) receptor γ2 subunit gene, GABRG2, have been associated with a variety of epilepsy syndromes. A de novo mutation (c.T1027C, p.F343L) in GABRG2 was identified in a patient with early onset epileptic encephalopathy. Zebrafish overexpressing mutant human GABRG2 (F343L) subunits displayed spontaneous seizure activity and convulsive behaviors. In this study, we demonstrated that Tg (hGABRG2F343L) zebrafish displayed hyperactivity during light phase with normal circadian rhythm, as well as increased drug-induced locomotor activity. Real-time quantitative PCR, whole mount in situ hybridization and western blotting showed that Tg(hGABRG2F343L) zebrafish had altered expression of GABAA receptor subunits. Furthermore, investigation of synaptic protein expression and synapse ultrastructure uncovered a robust synaptic phenotype that is causally linked to GABRG2(F343L) mutation. Strikingly, Tg(hGABRG2F343L) zebrafish not only had postsynaptic defects, but also displayed an unanticipated deficit at the presynaptic level. Overall, our Tg(hGABRG2F343L) overexpression zebrafish model has expanded the GABAergic paradigm in epileptic encephalopathy from channelopathy to synaptopathy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping