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- W634228546 abstract "OBJECTIVE: To identify and characterize the molecular basis of a CMS associated with intellectual disability, cortical hyperexcitability, and cerebellar ataxia in an 11-year-old girl. BACKGROUND: The SNARE proteins are core components of the synaptic vesicle fusion machinery. Ca 2+ -triggered exocytosis is initiated when synaptobrevin (a v-SNARE) attached to synaptic vesicles assembles with syntaxin and SNAP25B anchored in the presynaptic membrane (t-SNAREs) into an α-helical coiled-coil held together by hydrophobic interactions. SNAP25B is essential for vesicle docking, priming, and triggering fast exocytosis. A human mutation in SNAP25B caused epilepsy. DESIGN/METHODS: Clinical observations, microelectrode studies of neuromuscular transmission, exome sequencing, immunoblotting, liposome fusion assays, and amperometric assay of exocytosis. RESULTS: Exome sequencing identified a dominant de novo p.Ile67Asn mutation in SNAP25B. Endplate (EP) ultrastructure and expression of mutant SNAP25B in COS7 cells were normal. The miniature EP potential frequency was markedly reduced. The number of evoked quanta and the readily releasable fraction of quanta were not normally distributed, with some values significantly lower and some normal or higher than normal as can be observed with mutations arising in a post-zygotic cell. The probability of quantal release was 63 percent of normal. Expression studies showed the mutant SNAP25B expressed alone or in combination with wild-type SNAP25B (1) reduces depolarization-evoked exocytosis from bovine chromaffin cells to ~30[percnt] of that found after transfection with wild-type alone and (2) hinders the Ca 2+ triggered fusion of liposomes incorporating v-SNAREs with liposomes containing t-SNAREs. Treatment with 3,4-diaminopyridine improved the patient’s weakness but not her ataxia and caused no seizures. CONCLUSION: Ile67Asn mutation 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. Study Supported by: NIH Disclosure: Dr. Shen has nothing to disclose. Dr. Selcen has nothing to disclose. Dr. Brengman has nothing to disclose. Dr. Engel has nothing to disclose." @default.
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- W634228546 date "2015-04-06" @default.
- W634228546 modified "2023-09-23" @default.
- W634228546 title "Mutant SNAP25B Causes Novel Congenital Myasthenic Syndrome (CMS), Cortical Hyperexcitability, Ataxia, and Intellectual Disability (S34.003)" @default.
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