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

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

Journal: American journal of human genetics 2020;104(4):721-730

PMID: 30929742

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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.

Address: Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa 16132, Italy; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.; Department of Medical Genetics, Hospital Universitario Cruces, Greater Bilbao 48903, Spain.; Division of Human Genetics, Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3026, USA.; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa 16132, Italy.; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.; Division of Human Genetics, Department of the Adult and Developmental Age Human Pathology, University of Messina, Messina 98125, Italy.; Papardo University Hospital, Viale Ferdinando Stagno d'Alcontres, Contrada Papardo, Messina 98158, Italy.; Division of Child Neurology and Psychiatry, Department of the Adult and Developmental Age Human Pathology, University of Messina, Messina 98125, Italy.; Department of Pediatric Neurology, University Hospital Vall d'Hebron, Barcelona 08035, Spain.; Unidad de Enfermedades Mitocondriales-Metabólicas Hereditarias, Departamento de Pediatría, Hospital 12 de Octubre, Madrid 28041, Spain.; Laboratory of Neurogenetics and Neuroscience, G. Gaslini Institute, Genova 16147, Italy.; Center of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy.; Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy.; Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3026, USA.; Prince Hamzah Hospital, Ministry of Health, Amman 11181, Jordan.; Department of Pediatric Neurology, Institute of Child Health and The Children's Hospital Lahore, 381-D/2, Lahore 54600, Pakistan.; Department of Neuroradiology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.; Unité Fonctionnelle Innovation en Diagnostic Genomique des Maladies Rares, Center Hospitalier Universitaire Dijon Bourgogne, Dijon 21079, France; Inserm, UMR 1231, Genetique des Anomalies du Development, Université de Bourgogne, Dijon 21079, France.; Inserm, UMR 1231, Genetique des Anomalies du Development, Université de Bourgogne, Dijon 21079, France.; Inserm, UMR 1231, Genetique des Anomalies du Development, Université de Bourgogne, Dijon 21079, France; Center de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Dijon 21079, France.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid 28041, Spain.; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].; Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London WC1N 3BG, UK. Electronic address: [email protected].

DOI: 10.1016/j.ajhg.2019.02.016

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MeSH Terms: Adolescent, Autistic Disorder, Brain, Child, Child, Preschool, Epilepsy, Exocytosis, Female, Heterozygote, Humans, Intellectual Disability, Lipids, Magnetic Resonance Imaging, Male, Membrane Fusion, Movement Disorders, Muscle Hypotonia, Mutation, Neurodevelopmental Disorders, Neurons, Neurotransmitter Agents, Phenotype, Protein Domains, R-SNARE Proteins, Synapses, Vesicle-Associated Membrane Protein 2