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

Deciphering Developmental Disorders Study, SYNAPS Study Group

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)721-730
Number of pages10
JournalAmerican Journal of Human Genetics
Volume104
Issue number4
DOIs
Publication statusPublished - Apr 4 2019

Keywords

  • autism
  • epilepsy
  • movement disorders
  • neurodevelopmental disorders
  • neuronal exocytosis
  • SNARE
  • synaptobrevin
  • synaptopathy
  • VAMP2
  • vesicle fusion

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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