UNC13B variants associated with partial epilepsy with favourable outcome

Abstract

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13–2 (Munc13-2), that 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 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 favorable 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. Computational modeling, 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. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

FIBCD1 is a Conserved Receptor for Chondroitin Sulphate Proteoglycans of the Brain Extracellular Matrix and a Candidate Gene for a Complex Neurodevelopmental Disorder

“…In addition to FIBCD1 variants, P2's exome sequencing revealed additional variants of unknown significance (VUS) in UNC13B and RIC1. UNC13B encodes a pre-synaptic protein highly expressed in the brain, MUNC13-2, that has recently been associated with partial focal epilepsy 52 , not found in P2, and was therefore dismissed as potentially causative in this case. Variants in RIC1 gene have recently been associated with autosomal recessive CATIFA Syndrome (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder, OMIM: 618761) 50,51 .…”

CELSR3 variants are associated with febrile seizures and epilepsy with antecedent febrile seizures

“…To identify novel epilepsy‐associated gene, we put the known epilepsy‐associated genes aside, and selected the genes with de novo variants, biallelic variants, hemizygous variants, and variants with segregations for further studies to define the gene‐disease association, as we recently reported. 28 CELSR3 emerged as one of the candidate genes with recurrent de novo variants and variants with segregations in this cohort of patients. Conservation of mutated positions was evaluated using sequence alignment of different species.…”

Ketone Body Rescued Seizure Behavior Of LRP1 Deficiency By Modulating Glutamate Transport

“…It had been used to investigate the pathogenic genes for epilepsy and other neuro-development disorders [17,18]. Recently, we also used Drosophila as a model to discover the novel epilepsy gene-UNC13B [19]. Thus, we used Drosophila as a model here to study the role of LRP1 in epilepsy.…”

“…The LRP1 knockdown and control ies labeled with membrane GFP, tub-Gal4>UAS-mCD8::GFP/UAS-Unc13b-RNAi, and tub-Gal4>UAS-mCD8::GFP, were generated by UAS-mCD8::GFP and double balancer ies. The y brain was dissected, xed, and permeabilized following the previous description [19]. Samples were observed using a confocal microscope (SP8; Zeiss, Jena, Germany) and analyzed with ImageJ software (National Institutes of Health, Bethesda, MD, USA).…”