ArticleNeurology2014
Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability.
Article in Neurology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 2 of them syntheses that pooled it.
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Who cites it
66 citing papers in PubMed, 2 syntheses or guidelines pooled it, 126 citations in OpenAlex.
- Congenital myasthenic syndromes.Orphanet journal of rare diseases · 2019Pooled it
- High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.American journal of human genetics · 2017Pooled it
- Presynaptic Congenital Myasthenic Syndromes.Muscle & nerve · 2026Review
- The Differing Phenotypes of the Three Most Common Postsynaptic Congenital Myasthenic Syndromes Governed by Their Underlying Molecular Pathogenic Mechanisms.Muscle & nerve · 2026Review
- Review
- Arthrogryposis Multiplex Congenita: Comprehensive Review from a Neuromuscular Standpoint.Genes · 2026Review
- Proteomic profiling of ANO10-deficient SH-SY5Y cells reveals candidate pathways relevant to SCAR10.Scientific reports · 2026Article
- Fusion Pores as Regulators of Quantal Size and Cellular Physiology.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Review of 40 genes causing congenital myasthenic syndromes.Journal of human genetics · 2025Review
- The space-time continuum in neurological disorders of the autophagosome-lysosome fusion machinery.Autophagy reports · 2025Review
- Exploring the Landscape of Pre- and Post-Synaptic Pediatric Disorders with Epilepsy: A Narrative Review on Molecular Mechanisms Involved.International journal of molecular sciences · 2024Review
- Article
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models.Journal of neuromuscular diseases · 2023Review
- Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.Physiological reviews · 2023Review
- Genetic disorders of neurotransmitter release machinery.Frontiers in synaptic neuroscience · 2023Review
- Rapid genome sequencing identifies a novel de novoCold Spring Harbor molecular case studies · 2022Article
- Energetics, kinetics, and pathways of SNARE assembly in membrane fusion.Critical reviews in biochemistry and molecular biology · 2022Review
- A 6.3 Mb maternally derived microduplication of 20p13p12.2 in a fetus with Brachydactyly type D and related literature review.Molecular cytogenetics · 2022Article
- Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction.Frontiers in neurology · 2022Review
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
objectiveTo identify and characterize the molecular basis of a syndrome associated with myasthenia, cortical hyperexcitability, cerebellar ataxia, and intellectual disability.
methodsWe performed in vitro microelectrode studies of neuromuscular transmission, performed exome and Sanger sequencing, and analyzed functional consequences of the identified mutation in expression studies.
resultsNeuromuscular transmission at patient endplates was compromised by reduced evoked quantal release. Exome sequencing identified a dominant de novo variant, p.Ile67Asn, in SNAP25B, a SNARE protein essential for exocytosis of synaptic vesicles from nerve terminals and of dense-core vesicles from endocrine cells. Ca(2+)-triggered exocytosis is initiated when synaptobrevin attached to synaptic vesicles (v-SNARE) assembles with SNAP25B and syntaxin anchored in the presynaptic membrane (t-SNAREs) into an α-helical coiled-coil held together by hydrophobic interactions. Pathogenicity of the Ile67Asn mutation was confirmed by 2 measures. First, the Ca(2+) triggered fusion of liposomes incorporating v-SNARE with liposomes containing t-SNAREs was hindered when t-SNAREs harbored the mutant SNAP25B moiety. Second, depolarization of bovine chromaffin cells transfected with mutant SNAP25B or with mutant plus wild-type SNAP25B markedly reduced depolarization-evoked exocytosis compared with wild-type transfected cells.
conclusionIle67Asn variant in SNAP25B is pathogenic because it inhibits synaptic vesicle exocytosis. We attribute the deleterious effects of the mutation to disruption of the hydrophobic α-helical coiled-coil structure of the SNARE complex by replacement of a highly hydrophobic isoleucine by a strongly hydrophilic asparagine.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.