Howard Hughes Medical Institute and Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Howard Hughes Medical Institute and Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Neuron. 2020 Jul 8;107(1):52-64.e7. doi: 10.1016/j.neuron.2020.04.003. Epub 2020 May 1.
At neuronal synapses, synaptotagmin-1 (syt1) acts as a Ca sensor that synchronizes neurotransmitter release with Ca influx during action potential firing. Heterozygous missense mutations in syt1 have recently been associated with a severe but heterogeneous developmental syndrome, termed syt1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, we report the clinical, physiological, and biophysical characterization of three syt1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca-sensing domains of syt1. These mechanistic studies led to the discovery that a clinically approved K channel antagonist is able to rescue the dominant-negative heterozygous phenotype. Our results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder.
在神经元突触处，突触融合蛋白-1（syt1）作为钙传感器，在动作电位放电过程中，同步神经递质释放与钙内流。syt1 的杂合错义突变最近与一种严重但异质性的发育综合征相关，称为 syt1 相关神经发育障碍。该疾病中明确的发病机制和表型异质性的基础仍然未知。在这里，我们报告了来自人类患者的三种 syt1 突变的临床、生理和生物物理特征。表达突变变体的神经元中的突触传递受损，其表现出强大的、分级的显性负效应。对突变变体的生物物理检测揭示了关于 syt1 的串联钙感应结构域的协同作用和功能专业化的新的机制特征。这些机制研究导致发现一种临床批准的钾通道拮抗剂能够挽救杂合显性负表型。我们的结果确定了 syt1 相关神经发育障碍的分子病因、表型异质性的基础和潜在的治疗方法。
