In a screen for novel genetic variants in a cohort of 446 unrelated families with focal (partial) epilepsy, variants of the human gene UNC13B were identified in 12 individuals representing 8 different families. UNC13B encodes a member of the UNC13 family; genes in this family are involved in neurotransmitter release and synaptic vesicle maturation. There is a single orthologous gene in Drosophila, unc-13, for which multiple genetic reagents have been generated including classical hypomorphic alleles, RNAi-targeting constructs, overexpression constructs, and alleles caused by insertional mutagenesis. Dmel\unc-13 is also orthologous to human UNC13A and UNC13C.
The human UNC13B gene has not been introduced into flies. Note that in D. melanogaster, 'unc-13 A' and 'unc-13 B' refer to different isoforms of the single unc-13 gene; they do not correlate with UNC13A and UNC13B in human.
The more extreme loss-of-function mutations of Dmel\unc-13 are lethal as homozygotes; embryos exhibit with defects in neurophysiology and synaptic vesicles. To investigate adult phenotypes, the temperature sensitivity of RNAi-mediated knockdown was exploited. Under temperature-controlled conditions survival to the adult stage is observed; adult flies exhibit a bang-sensitive phenotype, a seizure-like phenotype observed for other seizure-related mutations in fly. The unc-13 knockdown bang-sensitive phenotype is less severe than that observed for a well-studied model of epilepsy in flies (see FBhh0000289); this is consistent with the milder epilepsy phenotype associated with UNC13B variants in human.
[updated Jan. 2022 by FlyBase; FBrf0222196]
Patients in this study were diagnosed with epilepsy that was characterized by focal seizures or focally originating secondary generalized tonic-clonic seizures. EEG recordings showed focal discharges with features of idiopathic epilepsy including shifting, bilateral or multiple focal discharges with normal background. The seizure onset age of the 12 affected individuals ranged from 3 months to 22 years old, with a median age of onset of 2 years. Five had febrile seizures, and none had intellectual or developmental abnormalities. (Wang et al., 2021; pubmed:33876820; FBrf0252014)
Dominant effects of variant alleles appear to explain most assessed cases; a compound heterozygous missense variant was implicated in one relatively severe case (Wang et al., 2021; pubmed:33876820; FBrf0252014).
UNC13B encodes a presynaptic protein which is highly expressed in the brain and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability (FBrf0252014 and references cited therein).
Many to one: 3 human genes to 1 Drosophila gene.
Moderate-scoring ortholog of human UNC13A, UNC13B, UNC13C (1 Drosophila to 3 human).
