Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
| Title: | Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment |
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| Authors: | Salpietro, Vincenzo; Malintan, Nancy T.; Llano-Rivas, Isabel; Spaeth, Christine G.; Efthymiou, Stephanie; Striano, Pasquale; Vandrovcova, Jana; Cutrupi, Maria C.; Chimenz, Roberto; David, Emanuele; Di Rosa, Gabriella; Marce-Grau, Anna; Raspall-Chaure, Miquel; Martin-Hernandez, Elena; Zara, Federico; Minetti, Carlo; Kriouile, Yamna; El Khorassani, Mohamed; Aguennouz, Mhammed; Karashova, Blagovesta; Avdjieva, Daniela; Kathom, Hadil; Tincheva, Radka; Van Maldergem, Lionel; Nachbauer, Wolfgang; Boesch, Sylvia; Arning, Larissa; Timmann, Dagmar; Cormand, Bru; Pérez-Dueñas, Belen; Pironti, Erica; Goraya, Jatinder S.; Sultan, Tipu; Kirmani, Salman; Ibrahim, Shahnaz; Jan, Farida; Mine, Jun; Banu, Selina; Veggiotti, Pierangelo; Ferrari, Michel D.; Verrotti, Alberto; Marseglia, Gian Luigi; Savasta, Salvatore; Garavaglia, Barbara; Scuderi, Carmela; Borgione, Eugenia; Dipasquale, Valeria; Cutrupi, Maria Concetta; Portaro, Simona; Sanchez, Benigno Monteagudo; Pineda-Marfa, Mercedes; Munell, Francina; Macaya, Alfons; Boles, Richard; Heimer, Gali; Papacostas, Savvas; Manole, Andreea; Malintan, Nancy; Zanetti, Maria Natalia; Hanna, Michael G.; Rothman, James E.; Kullmann, Dimitri M.; Houlden, Henry; Bello, Oscar D.; De Zorzi, Rita; Fortuna, Sara; Dauber, Andrew; Alkhawaja, Mariam; Mankad, Kshitij; Vitobello, Antonio; Thomas, Quentin; Mau-Them, Frederic Tran; Faivre, Laurence; Martinez-Azorin, Francisco; Prada, Carlos E.; Krishnakumar, Shyam S. |
| Contributors: | Salpietro, Vincenzo; Malintan, Nancy T.; Llano-Rivas, Isabel; Spaeth, Christine G.; Efthymiou, Stephanie; Striano, Pasquale; Vandrovcova, Jana; Cutrupi, Maria C.; Chimenz, Roberto; David, Emanuele; Di Rosa, Gabriella; Marce-Grau, Anna; Raspall-Chaure, Miquel; Martin-Hernandez, Elena; Zara, Federico; Minetti, Carlo; Kriouile, Yamna; El Khorassani, Mohamed; Aguennouz, Mhammed; Karashova, Blagovesta; Avdjieva, Daniela; Kathom, Hadil; Tincheva, Radka; Van Maldergem, Lionel; Nachbauer, Wolfgang; Boesch, Sylvia; Arning, Larissa; Timmann, Dagmar; Cormand, Bru; Pérez-Dueñas, Belen; Pironti, Erica; Goraya, Jatinder S.; Sultan, Tipu; Kirmani, Salman; Ibrahim, Shahnaz; Jan, Farida; Mine, Jun; Banu, Selina; Veggiotti, Pierangelo; Ferrari, Michel D.; Verrotti, Alberto; Marseglia, Gian Luigi; Savasta, Salvatore; Garavaglia, Barbara; Scuderi, Carmela; Borgione, Eugenia; Dipasquale, Valeria; Cutrupi, Maria Concetta; Portaro, Simona; Sanchez, Benigno Monteagudo; Pineda-Marfa, Mercede; Munell, Francina; Macaya, Alfon; Boles, Richard; Heimer, Gali; Papacostas, Savva; Manole, Andreea; Malintan, Nancy; Zanetti, Maria Natalia; Hanna, Michael G.; Rothman, James E.; Kullmann, Dimitri M.; Houlden, Henry; Bello, Oscar D.; De Zorzi, Rita; Fortuna, Sara; Dauber, Andrew; Alkhawaja, Mariam; Mankad, Kshitij; Vitobello, Antonio; Thomas, Quentin; Mau-Them, Frederic Tran; Faivre, Laurence; Martinez-Azorin, Francisco; Prada, Carlos E.; Krishnakumar, Shyam S. |
| Publisher Information: | CELL PRESS |
| Publication Year: | 2019 |
| Collection: | Università degli Studi di Messina: IRIS |
| Subject Terms: | autism; epilepsy; movement disorders; neurodevelopmental disorders; neuronal exocytosis; SNARE; synaptobrevin; synaptopathy; VAMP2; vesicle fusion; Genetics; Genetics (clinical) |
| Description: | VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synap- tosomal-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 pre- sent since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-syn- onymous 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. Recon- stituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mecha- nisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function. |
| Document Type: | article in journal/newspaper |
| File Description: | STAMPA |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/30929742; info:eu-repo/semantics/altIdentifier/wos/WOS:000463474700012; volume:104; issue:4; firstpage:721; lastpage:730; numberofpages:10; journal:AMERICAN JOURNAL OF HUMAN GENETICS; https://hdl.handle.net/11570/3138980 |
| DOI: | 10.1016/j.ajhg.2019.02.016 |
| Availability: | https://hdl.handle.net/11570/3138980; https://doi.org/10.1016/j.ajhg.2019.02.016; https://www.cell.com/ajhg/fulltext/S0002-9297(19)30061-8 |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.13D80486 |
| Database: | BASE |