Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Am J Hum Genet. 2019 Apr 4;104(4):721-730. doi: 10.1016/j.ajhg.2019.02.016. Epub 2019 Mar 28.


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.

Keywords: SNARE; VAMP2; autism; epilepsy; movement disorders; neurodevelopmental disorders; neuronal exocytosis; synaptobrevin; synaptopathy; vesicle fusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism
  • Brain / diagnostic imaging
  • Child
  • Child, Preschool
  • Epilepsy / metabolism
  • Exocytosis
  • Female
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics*
  • Lipids / chemistry
  • Magnetic Resonance Imaging
  • Male
  • Membrane Fusion
  • Movement Disorders / genetics
  • Muscle Hypotonia / genetics*
  • Mutation
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / metabolism
  • Neurons / metabolism*
  • Neurotransmitter Agents / metabolism
  • Phenotype
  • Protein Domains
  • R-SNARE Proteins / metabolism
  • Synapses / metabolism*
  • Vesicle-Associated Membrane Protein 2 / genetics*
  • Vesicle-Associated Membrane Protein 2 / physiology


  • Lipids
  • Neurotransmitter Agents
  • R-SNARE Proteins
  • VAMP2 protein, human
  • Vesicle-Associated Membrane Protein 2