Date Published: April 04, 2019
Author(s): Vincenzo Salpietro, Nancy T. Malintan, Isabel Llano-Rivas, Christine G. Spaeth, Stephanie Efthymiou, Pasquale Striano, Jana Vandrovcova, Maria C. Cutrupi, Roberto Chimenz, Emanuele David, Gabriella Di Rosa, Anna Marce-Grau, Miquel Raspall-Chaure, Elena Martin-Hernandez, Federico Zara, Carlo Minetti, Oscar D. Bello, Rita De Zorzi, Sara Fortuna, Andrew Dauber, Mariam Alkhawaja, Tipu Sultan, Kshitij Mankad, Antonio Vitobello, Quentin Thomas, Frederic Tran Mau-Them, Laurence Faivre, Francisco Martinez-Azorin, Carlos E. Prada, Alfons Macaya, Dimitri M. Kullmann, James E. Rothman, Shyam S. Krishnakumar, Henry Houlden.
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.
Chemical synaptic transmission relies on precisely coordinated, activity-dependent neurotransmitter release.1 A fundamental step in this pathway is the fusion of synaptic vesicles with the presynaptic plasma membrane. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins mediate membrane fusion and are essential for the fusion of synaptic vesicles.1, 2 At mammalian central nervous system (CNS) synapses, neuronal SNAREs consist of vesicle-associated membrane protein 2 (VAMP2, also called synaptobrevin-2) on the vesicle membrane (v-SNARE) and the binary complex of syntaxin1A (STX1A) and synaptosomal-associated protein 25 Kd (SNAP25) on the plasma membrane (target or t-SNARE).3 The v- and t-SNARE proteins assemble in a polarized manner starting from the N termini distal from the membranes and proceeding towards the C termini and are held together by discrete interacting residues (numbered -7 to +8), including 15 hydrophobic contacts and central ionic residues.4 This “zippering” process pulls the membranes together and provides the energy to fuse the lipid bilayers.5, 6 The SNAREs alone are sufficient to drive fusion of synaptic vesicles, but this process is tightly regulated by a number of synaptic proteins to enable Ca2+-regulated neurotransmitter release.7 The key regulatory elements at excitatory CNS synapses include chaperones (Munc18 and Munc13), the primary Ca2+ sensor synaptotagmin-1, and the auxiliary protein complexin.7, 8, 9, 10
The authors declare no competing interests.