Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling
Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling
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DOI：
10.1172/jci79765
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发表时间：
2015-04-01
影响因子：
15.9
通讯作者：
Raymond, F. Lucy
中科院分区：
文献类型：
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作者：
Baker, Kate;Gordon, Sarah L.;Raymond, F. Lucy
突触结合蛋白-1（SYT 1）是一种钙结合突触囊泡蛋白，是胞吐和胞吞作用所必需的。在这里，我们描述了一种与SYT 1罕见变异相关的人类疾病。携带这种变异的个体表现为早发性运动障碍、严重的运动延迟和严重的认知障碍。结构MRI正常，但EEG显示广泛的神经生理紊乱，包括低频振荡爆发和视觉诱发电位增强的成对脉冲抑制的不寻常特征。全外显子序列的Trio分析鉴定了一个新的SYT 1错义变体（I368 T）。在WT小鼠原代海马培养物中表达含有等效人类变体的大鼠SYT 1揭示了SYT 1的突变形式正确地定位于神经末梢，并且以近似等于内源性WT蛋白水平的水平表达。突变SYT 1的存在减缓了突触囊泡融合动力学，这一发现与先前证明的I368在钙依赖性膜渗透中的作用一致。I368 T变体的表达也改变了突触囊泡内吞的动力学。总之，与这种显性负SYT 1突变相关的临床特征、电生理表型和体外神经元表型突出了介导人类运动控制和认知发育的突触前机制。
Synaptotagmin-1(SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development.