De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Klöckner, Chiara; Sticht, Heinrich; Zacher, Pia; Popp, Bernt; Babcock, Holly E.; Bakker, Dewi P.; Barwick, Katy; Bonfert, Michaela; Bönnemann, Carsten G.; Brilstra, Eva H.; Chung, Wendy K.; Devine, Patrick; Donkervoort, Sandra; Fraser, Jamie L.; Friedman, Jennifer; Gates, Alyssa; Ghoumid, Jamal; Hobson, Emma; Horváth, Gabriella; Keller‐Ramey, Jennifer; Keren, Boris; Kurian, Manju A.; Lee, Virgina; Leppig, Kathleen A.; Lundgren, Johan; McDonald, Marie; McTague, Amy; Mefford, Heather C; Mignot, Cyril; Mikati, Mohamad A.; Nava, Caroline; Raymond, F. Lucy; Sampson, Julian R.; Sanchis-Juan, Alba; Shashi, Vandana; Shieh, Joseph T.C.; Shinawi, Marwan; Slavotinek, Anne; Stödberg, Tommy; Stong, Nicholas; Sullivan, Jennifer; Taylor, Ashley C.; Toler, Tomi L.; Boogaard, M.; Crabben, Saskia N. van der; Gassen, Koen van; Jaarsveld, Richard H. van; Ziffle, Jessica Van; Wadley, Alexandrea; Wagner, Matias; Wigby, Kristen; Wortmann, Saskia B.; Zárate, Yuri A.; Møller, Rikke S.; Lemke, Johannes R.; Platzer, Konrad

doi:10.1038/s41436-020-01020-w

Cited by 32 publications

(22 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Morphology of the brain appeared normal ( 38 ). There have been 19 different de novo mutations identified so far in SNAP25 across 23 patients ( 39 ). Out of the total number of variants, 14 were missense, 2 nonsense and 2 splice-site ( Table 1 ).…”

Section: Proteins Of the Main Snare Complexmentioning

confidence: 99%

Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

et al. 2022

View full text Add to dashboard Cite

SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptor) are an heterogeneous family of proteins that, together with their key regulators, are implicated in synaptic vesicle exocytosis and synaptic transmission. SNAREs represent the core component of this protein complex. Although the specific mechanisms of the SNARE machinery is still not completely uncovered, studies in recent years have provided a clearer understanding of the interactions regulating the essential fusion machinery for neurotransmitter release. Mutations in genes encoding SNARE proteins or SNARE complex associated proteins have been associated with a variable spectrum of neurological conditions that have been recently defined as “SNAREopathies.” These include neurodevelopmental disorder, autism spectrum disorder (ASD), movement disorders, seizures and epileptiform abnormalities. The SNARE phenotypic spectrum associated with seizures ranges from simple febrile seizures and infantile spasms, to severe early-onset epileptic encephalopathies. Our study aims to review and delineate the epileptic phenotypes associated with dysregulation of synaptic vesicle exocytosis and transmission, focusing on the main proteins of the SNARE core complex (STX1B, VAMP2, SNAP25), tethering complex (STXBP1), and related downstream regulators.

show abstract

Section: Proteins Of the Main Snare Complexmentioning

confidence: 99%

Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Syntaxin1 (Stx1) is a protein widely expressed in the nervous system ( 12 , 13 ) and, together with Snap25 (encoded by SNAP25 ) and synaptobrevin-2 (encoded by VAMP 2), form a stable complex called soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) complex, made by a four-helix bundle implicated in Ca 2+ -dependent exocytosis of the synaptic vesicles and neurotransmitter release ( 14 , 15 ). Vamp2 protein represents the vesicle membrane portion of SNARE neuronal complex (v-SNARE), while the plasma membrane of SNARE (t-SNARE) is constituted by Stx1a and Snap25 ( 16 ).…”

Section: Stx1bmentioning

confidence: 99%

“…We reviewed the recent literature and found the description of 18 cases in which pathogenic variants of SNAP25 are associated with DEEs (15,(44)(45)(46)(47). All clinical data are summarized in Table 2.…”

Section: Snap25mentioning

confidence: 99%

See 1 more Smart Citation

Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction

et al. 2022

View full text Add to dashboard Cite

The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as “synaptopathy.” Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.

show abstract

“…Crystal structures of the SYT1-SNARE complex (PDB: 5CCH, 5CCG and 5KJ7) 20 show that Asn341 may interact directly with Asp166 of SNAP-25 or form a hydrogen bond with the neighboring Tyr339 in SYT1, which binds Asp166 of SNAP-25 (Figure 2i). Interestingly, two variants at Asp166 have been identified in individuals with SNAP25 developmental and epileptic encephalopathy 21 .…”

Section: Figure 2 Predicted Molecular Impacts Of Newly-identified Syt1 Variantsmentioning

confidence: 99%

Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

Melland

Bumbak

Kolesnik-Taylor

et al. 2021

Preprint

View full text Add to dashboard Cite

PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.ResultsFour variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.ConclusionSYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.

show abstract

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Abstract: NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 32 publications

References 42 publications

Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction

Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

Contact Info

Product

Resources

About