SNAREopathies: Diversity in Mechanisms and Symptoms
Open accessAbstract
Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmission as a single integrated membrane fusion machine. Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syndromes. We propose to unify these syndromes, based on etiology and mechanism, as "SNAREopathies." Here, we review the strikingly diverse clinical phenomenology and disease severity and the also remarkably diverse genetic mechanisms. We argue that disease severity generally scales with functional redundancy and, conversely, that the large effect of mutations in some SNARE genes is the price paid for extensive integration and exceptional specialization. Finally, we discuss how subtle differences in components being rate limiting in different types of neurons helps to explain the main symptoms.
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Complexin II plays a positive role in Ca 2+ -triggered exocytosis by facilitating vesicle priming
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Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia
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The RAB3-RIM pathway is essential for the release of neuromodulators
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Self-citationMunc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation
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Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder
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Self-citationMutation inSNAP25as a novel genetic cause of epilepsy and intellectual disability
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Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy
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Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission
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Self-citationElectrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome
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SNAP-25 gene family members differentially support secretory vesicle fusion
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Self-citationAn Autaptic Culture System for Standardized Analyses of iPSC-Derived Human Neurons
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Self-citationClinical spectrum of STX1B -related epileptic disorders
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Self-citationPaternal mosaicism of an STXBP1 mutation in OS
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Acute Complexin Knockout Abates Spontaneous and Evoked Transmitter Release
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Haploinsufficiency of the STX1B gene is associated with myoclonic astatic epilepsy
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Hemizygous deletion of the HPC-1/syntaxin 1A gene (STX1A) in patients with Williams syndrome
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An Electrostatic Energy Barrier for SNARE-Dependent Spontaneous and Evoked Synaptic Transmission
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Genetic enhancement of cognition in a kindred with cone–rod dystrophy due to RIMS1 mutation
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Flagged first, then by citations
Research works printed but not linked: 2
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Cited by
Sorted by citations
Assessing the landscape of <i>STXBP1</i> -related disorders in 534 individuals
Xian, J., Parthasarathy, S., Ruggiero, S. M., Balagura, G., Fitch, E., Helbig, K., Gan, J., Ganesan, S., Kaufman, M. C., Ellis, C. A., et al. (2022) · Brain · doi:10.1093/brain/awab327 · Cited by 130 · see citing works
Self-citationDevelopmental and epileptic encephalopathies
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Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
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De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy
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- Authors
- Verhage, M., & Sørensen, J. B.
- Affiliations
- Amsterdam University Medical Centers (NL)
- University of Copenhagen (DK)
- Corresponding author
- Verhage, Matthijs
- Sørensen, Jakob B.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 107
- Issue
- 1
- Pages
- 22-37
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W3035920737
- Cited by
- 121
- References
- 136
- Citations by year
- 2026: 22 · 2025: 18 · 2024: 19 · 2023: 26 · 2022: 23 · 2021: 7 · 2020: 6
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Danmarks Frie Forskningsfond (8020-00228A)
- Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania (MDBR-20-136-STXBP1)
- European Research Council (322966)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.004.012)
- Lundbeckfonden (R277-2018-802)
- Novo Nordisk Fonden (NNF17OC0028516)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- SNARE proteins, synaptic vesicle exocytosis, synaptic transmission, membrane fusion, neurodevelopmental syndrome, functional redundancy, disease severity
- MeSH terms
- Humans, Mutation, SNARE Proteins, Neurodevelopmental Disorders
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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