SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.

SNARE（可溶性N-ethylmaleimide 敏感因子附着蛋白受体）复合物，由 synaptobrevin、syntaxin 和 SNAP25 组成，形成神经递质释放的基本融合机​​制。最近的研究报告了编码 SNAP25 的基因中的几个突变，这些突变是具有不同临床表现的婴儿期和儿童期发育性和癫痫性脑病的致病因素。然而，目前尚不清楚 SNAP25 突变如何导致这些疾病。在这里，我们表明，尽管 SNAP25 中的结构聚类突变导致相关的突触传递表型，但自发神经递质释放的特定改变是解释疾病异质性的关键因素。重要的是，我们发现了一种突变，它可以在不改变诱发释放的情况下增加自发释放，