6533b82efe1ef96bd12923d0
RESEARCH PRODUCT
Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
Vincenzo SalpietroNancy T MalintanIsabel Llano-rivasChristine G SpaethStephanie EfthymiouPasquale StrianoJana VandrovcovaMaria C CutrupiRoberto ChimenzEmanuele DavidGabriella Di RosaAnna Marce-grauMiquel Raspall-chaureElena Martin-hernandezFederico ZaraCarlo MinettiOscar D BelloRita De ZorziSara FortunaAndrew DauberMariam AlkhawajaTipu SultanKshitij MankadAntonio VitobelloQuentin ThomasFrederic Tran Mau-themLaurence FaivreFrancisco Martinez-azorinCarlos E PradaAlfons MacayaDimitri M KullmannJames E RothmanShyam S KrishnakumarHenry HouldenVincenzo SalpietroStephanie EfthymiouYamna KriouileMohamed El KhorassaniMhammed AguennouzBlagovesta KarashovaDaniela AvdjievaHadil KathomRadka TinchevaLionel Van MaldergemWolfgang NachbauerSylvia BoeschLarissa ArningDagmar TimmannBru CormandBelen Pérez-dueñasGabriella Di RosaErica PirontiJatinder S GorayaTipu SultanSalman KirmaniShahnaz IbrahimFarida JanJun MineSelina BanuPierangelo VeggiottiMichel D FerrariAlberto VerrottiGian Luigi MarsegliaSalvatore SavastaBarbara GaravagliaCarmela ScuderiEugenia BorgioneValeria DipasqualeMaria Concetta CutrupiSimona PortaroBenigno Monteagudo SanchezMercedes Pineda-marfa’Francina MunellAlfons MacayaRichard BolesGali HeimerSavvas PapacostasAndreea ManoleNancy MalintanMaria Natalia ZanettiMichael G HannaJames E RothmanDimitri M KullmannHenry. Houldensubject
MaleHeterozygoteAdolescentVesicle-Associated Membrane Protein 2neuronal exocytosisynaptopathyautismsynaptobrevinMembrane FusionExocytosisR-SNARE ProteinsProtein DomainsReportIntellectual DisabilityGeneticsHumansAutistic DisorderChildGenetics (clinical)NeuronsNeurotransmitter Agentsneurodevelopmental disordersvesicle fusionBrainautism; epilepsy; movement disorders; neurodevelopmental disorders; neuronal exocytosis; SNARE; synaptobrevin; synaptopathy; VAMP2; vesicle fusionneuronal exocytosisLipidsMagnetic Resonance Imagingneurodevelopmental disorderautism epilepsy movement disorders neurodevelopmental disorders neuronal exocytosis SNARE synaptobrevin synaptopathy VAMP2 vesicle fusion Genetics Genetics (clinical)Phenotypeautism; epilepsy; movement disorders; neurodevelopmental disorders; neuronal exocytosis; SNARE; synaptobrevin; synaptopathy; VAMP2; vesicle fusion; Genetics; Genetics (clinical)VAMP2SNAREChild PreschoolMutationSynapsesMuscle Hypotoniaepilepsymovement disordersFemalesense organsmovement disorderdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-03-01 |