Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 510260, China.
Brain. 2021 Nov 29;144(10):3050-3060. doi: 10.1093/brain/awab164.
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.
UNC13B 基因编码一种突触前蛋白，哺乳动物未协调 13-2（Munc13-2），在大脑中高度表达，主要在大脑皮层中，并在突触囊泡引发和融合中发挥重要作用，可能影响神经元兴奋性。然而，UNC13B 突变在人类疾病中的功能意义尚不清楚。在这项研究中，我们通过基于 trio 的全外显子组测序对 446 名无获得性病因的部分性癫痫无关病例（家族）进行了新型遗传变异的筛查。在来自 8 个无关家庭的 12 名受部分性癫痫和/或热性惊厥影响的个体中鉴定出 UNC13B 变体。8 名先证者均有局灶性癫痫和脑电图记录中的局灶性放电，包括 2 名经常每日发作的患者和 1 名脑 MRI 显示海马异常的患者；然而，所有患者均无智力或发育异常的良好预后。鉴定出的 UNC13B 变体包括一个无义变体、两个位于或接近剪接位点的变体、一个复合杂合错义变体和四个在家族中共分离的错义变体。本研究中鉴定的 UNC13B 变体的频率明显高于汉族对照人群和东亚人群以及基因组聚集数据库（gnomAD）中的所有人群的 UNC13B 变体频率。包括氢键和对接分析的计算建模表明，这些变体导致功能障碍。与野生型果蝇相比，UNC13B 敲低导致果蝇的癫痫发作率和持续时间增加，但这些影响不如钠电压门控通道 alpha 亚基 1（Scn1a）敲低果蝇明显。电生理记录显示，UNC13b 缺陷果蝇中的兴奋性神经元兴奋性增加。这些结果表明 UNC13B 可能与癫痫有关。我们患者的抗癫痫治疗下频繁的每日发作和海马异常但最终良好的预后表明，由 UNC13B 变体引起的部分性癫痫是一种临床可管理的病症。
