Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment

Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle‐associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For...

Full description

Saved in:

Bibliographic Details
Published in:	Human mutation Vol. 41; no. 11; pp. 1999 - 2011
Main Authors:	Simmons, Roxanne L., Li, Haiyan, Alten, Baris, Santos, Magda S., Jiang, Ruiji, Paul, Brianna, Lalani, Sanam J., Cortesi, Audrey, Parks, Kendall, Khandelwal, Nitin, Smith‐Packard, Bethany, Phoong, Malay A., Chez, Michael, Fisher, Heather, Scheuerle, Angela E., Shinawi, Marwan, Hussain, Shaun A., Kavalali, Ege T., Sherr, Elliott H., Voglmaier, Susan M.
Format:	Journal Article
Language:	English
Published:	United States Hindawi Limited 01-11-2020
Subjects:	4-Aminopyridine - pharmacology Adult aminopyridine Autism Cognitive ability Electrophysiology Emotional behavior Epilepsy Exocytosis Exocytosis - drug effects Female Humans Male Membrane proteins Mutation Mutation - genetics neurodevelopmental disorder Neurotransmission Patients synaptic transmission Synaptic Transmission - drug effects synaptic vesicle Synaptic vesicles Synaptic Vesicles - drug effects Synaptic Vesicles - metabolism Synchronization VAMP2 Vesicle-Associated Membrane Protein 2 - genetics γ-Aminobutyric acid synaptic transmission neurodevelopmental disorder VAMP2 aminopyridine synaptic vesicle
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle‐associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop‐gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4‐aminopyridine and 3,4‐diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live‐cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild‐type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off‐label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment. A precision medicine approach to neurodevelopmental disorder in patients with mutations in the synaptic vesicle protein VAMP2 investigated variant effects on vesicle recycling and synaptic transmission in cellular models. A treatment strategy to enhance neurotransmission by increasing vesicle release was tested in vitro and in vivo.
Bibliography:	Roxanne L. Simmons, Haiyan Li, and Baris Alten contributed equally to this study. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. CONTRIBUTORS SMV, EHS, and ETK conceived, designed, and supervised the study; all authors were involved in acquisition, analysis, interpretation of data; RLS, SMV, EHS, ETK, BA and HL drafted and critically revised the manuscript for important intellectual content; SMV and EHS are responsible for the overall content of the manuscript. RLS, HL and BA are joint first authors. SMV and EHS are joint corresponding authors.
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.24109