Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Wellcome Trust / MRC Building, Hills Road, Cambridge, UK.
MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge, UK.
Brain. 2018 Sep 1;141(9):2576-2591. doi: 10.1093/brain/awy209.
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.
突触结合蛋白 1（SYT1）是快速、同步、钙依赖性神经递质释放的关键介质，也调节突触小泡内吞作用。本文描述了 11 例新发性杂合错义突变的 SYT1 患者。所有突变均改变高度保守的残基，并聚集在 SYT1 C2B 结构域的两个区域，位置为 Met303（M303K）、Asp304（D304G）、Asp366（D366E）、Ile368（I368T）和 Asn371（N371K）。表型特征包括婴儿期低张力、先天性眼部异常、儿童期起病的多动运动障碍、运动刻板动作和严重程度从中度到重度的发育迟缓。行为特征包括睡眠障碍和阵发性激越。无癫痫发作和正常眶额头围是重要的阴性特征。结构 MRI 无明显异常，但 EEG 干扰是普遍存在的，表现为间歇性低频高振幅振荡。通过在野生型小鼠海马原代培养物中表达含有等效人类变异的大鼠 SYT1 蛋白，评估了这 5 种新发性 SYT1 突变的功能影响。所有突变形式的 SYT1 表达水平约等于内源性野生型蛋白，并且在静止时正确定位于神经末梢，除了 SYT1M303K，其表达水平较低且未能在神经末梢定位于神经末梢。刺激后，SYT1I368T 和 SYT1N371K 至少像野生型 SYT1 一样有效地重新定位于神经末梢。然而，SYT1D304G 和 SYT1D366E 未能在刺激后重新定位于神经末梢，表明 SYT1 内吞作用的再循环和运输受损。此外，神经末梢存在 SYT1 变体诱导持续动作电位刺激后的出胞率减慢。受影响个体表型的严重程度反映了突触小泡动力学的干扰程度，表明 SYT1 介导的神经递质释放效率对认知发育至关重要。总之，新发性显性 SYT1 错义突变与可识别的神经发育综合征相关，现在可以根据临床特征、电生理特征和突变特征诊断进一步的病例。表型严重程度的变化可能反映了突变对 SYT1 多种生理功能的特异性影响。
