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UNC13B variants associated with partial epilepsy with favourable outcome
- Source :
- Brain
- Publication Year :
- 2021
-
Abstract
- The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.<br />Wang et al. present clinical and experimental evidence suggesting that UNC13B is a novel epilepsy gene. They describe UNC13B mutations in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families, and show seizure-like behaviour and increased neural firing in Unc13b knockdown flies.
- Subjects :
- Proband
Adult
Male
Adolescent
Hippocampus
Nerve Tissue Proteins
Biology
Compound heterozygosity
Bioinformatics
medicine.disease_cause
Drosophila knockdown model
Animals, Genetically Modified
Epilepsy
UNC13B
medicine
Missense mutation
Animals
Humans
Amino Acid Sequence
Child
Loss function
Mutation
AcademicSubjects/SCI01870
Genetic Variation
Original Articles
medicine.disease
electrophysiology
Treatment Outcome
loss of function
Child, Preschool
AcademicSubjects/MED00310
Drosophila
Female
Neurology (clinical)
Epilepsies, Partial
partial epilepsy
Synaptic vesicle priming
Subjects
Details
- ISSN :
- 14602156
- Volume :
- 144
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Brain : a journal of neurology
- Accession number :
- edsair.doi.dedup.....2fa099bf8721febbc8c453830e38a8f0