Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
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DOI：
10.1016/j.ajhg.2019.02.016
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发表时间：
2019-04-04
影响因子：
9.8
通讯作者：
Houlden, Henry
中科院分区：
文献类型：
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作者：
Salpietro, Vincenzo;Malintan, Nancy T.;Houlden, Henry
VAMP2 编码囊泡 SNARE 蛋白 VAMP2（也称为 synaptobrevin-2）。 VAMP2 与其伙伴 Syntaxin-1A 和突触体相关蛋白 25 (SNAP25) 一起介导突触小泡的融合以释放神经递质。 VAMP2 对于囊泡胞吐作用和活动依赖性神经递质释放至关重要。在此，我们报告了无关个体中 VAMP2 的 5 个杂合从头突变，这些个体患有神经发育障碍，其特征是轴性肌张力低下（自出生以来就存在）、智力障碍和自闭症特征。总的来说，我们鉴定了两个单氨基酸缺失和三个影响 VAMP2 SNARE 基序 C 末端保守残基的非同义变异。携带涉及 C 末端区域的从头非同义变异的受影响个体表现出更严重的表型，并具有额外的神经学特征，包括中枢视觉障碍、多动性运动障碍、癫痫或脑电图异常。涉及脂质混合测定的重构融合表明囊泡融合受损是可能的相关疾病机制之一。 VAMP2从头突变引起的遗传突触病凸显了该基因在人类大脑发育和功能中的关键作用。
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.