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Abstract：
Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals\' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.
摘要：
Synaptotagmin1(SYT1)是快速的关键介体，同步,钙依赖性神经递质释放，还调节突触小泡胞吞作用。本文描述了11例SYT1中从头杂合错义突变的患者。所有突变都会改变高度保守的残基，并聚集在SYT1C2B域的两个区域中，位置为Met303（M303K），Asp304(D304G),Asp366(D366E),Ile368(I368T)和Asn371(N371K)。表型特征包括婴儿张力减退，先天性眼科异常，儿童期发作的多动运动障碍，运动刻板印象，发育迟缓的严重程度从中度到深度不等。行为特征包括睡眠障碍和偶发性激动。没有癫痫发作和正常的眶额头围是重要的负面特征。结构MRI不显著，但脑电图紊乱是普遍的，以间歇性低频高振幅振荡为特征。已通过在野生型小鼠原代海马培养物中表达含有等效人变体的大鼠SYT1蛋白来评估这五个从头SYT1突变的功能影响。SYT1的所有突变形式都以大约等于内源性野生型蛋白的水平表达。并在休息时正确定位到神经末梢，除了SYT1M303K，在较低水平表达，未能定位在神经末梢。在刺激之后,SYT1I368T和SYT1N371K至少与野生型SYT1一样有效地重新定位到神经末梢。然而,SYT1D304G和SYT1D366E在刺激后未能重新定位到神经末梢，指示SYT1的内吞取回和运输受损。此外,持续动作电位刺激后,神经末梢SYT1变异体的存在导致胞吐率减慢.受影响个体表型的严重程度反映了突触小泡动力学的紊乱程度，这表明SYT1介导的神经递质释放的效率对认知发育至关重要。总之,从头显性SYT1错义突变与可识别的神经发育综合征有关，现在可以根据临床特征诊断更多的病例，电生理特征和突变特征。表型严重性的变化可以反映对SYT1的不同生理功能的突变特异性影响。
