Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Schubert, Julian; Siekierska, Aleksandra; Langlois, Mélanie; May, Patrick; Huneau, Clément; Becker, Felicitas; Muhle, Hiltrud; Suls, Arvid; Lemke, Johannes R.; Kovel, Carolien G.F. de; Thiele, Holger; Konrad, Kathryn; Kawalia, Amit; Toliat, Mohammad Reza; Sander, Thomas; Rüschendorf, Franz; Caliebe, Almuth; Nagel, Inga; Kohl, Bernard; Kecskés, Angela; Jacmin, Maxime; Hardies, Katia; Weckhuysen, Sarah; Riesch, Erik; Dorn, Thomas; Brilstra, Eva H.; Baulac, Stéphanie; Møller, Rikke S.; Hjalgrim, Helle; Koeleman, Bobby P. C.; Jurkat‐Rott, Karin; Lehman-Horn, Frank; Roach, Jared C.; Glusman, Gustavo; Hood, Leroy; Galas, David J.; Martin, Benoı̂t; Witte, Peter de; Biskup, Saskia; Jonghe, Peter De; Helbig, Ingo; Balling, Rudi; Nürnberg, Peter; Crawford, Alexander D.; Esguerra, Camila V.; Weber, Yvonne G.; Lerche, Holger

doi:10.1038/ng.3130

Cited by 177 publications

(141 citation statements)

References 44 publications

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“…For details on coverage and called variants see Supplementary Table 3. All subsequent analyses were performed using the family WGS analysis pipeline as previously described 84 . In short, as input for the WGS analysis pipeline, we first combined all the variants from all genomes of one family into the union of variants using the CGAtools (CG Analysis Tools) listvariant command and CG var-files as input.…”

Section: Methodsmentioning

confidence: 99%

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

et al. 2016

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The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra-and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease.

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Section: Methodsmentioning

confidence: 99%

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

et al. 2016

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“…These include mutations in syntaxin‐1B (STX1B), SNAP‐25, and syntaxin binding protein 1 (STXBP1/Munc 18‐1) (Rohena et al., 2013; Saitsu, Kato, Mizuguchi, Hamada, & Osaka, 2008; Schubert, Siekierska, Langlois, May, & Huneau, 2014). The current study of kindling facilitation in a viable STXBP5/tomosyn‐1‐deficient mouse suggests another potential synaptopathy that has not been described in humans.…”

Section: Discussionmentioning

confidence: 99%

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

et al. 2017

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IntroductionIn kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn‐1, in kindling.MethodsStimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild‐type and STXBP5/tomosyn‐1−/− (Tom−/−) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate‐selective microelectrode array (MEA).ResultsNaïve Tom−/− mice had significant increases in KCl‐evoked glutamate release compared to naïve wild type as measured by MEA of presynaptic release in the hippocampal dentate gyrus (DG). Kindling progression was considerably accelerated in Tom−/− mice, requiring fewer stimuli to reach a fully kindled state. Following full kindling, MEA measurements of both kindled Tom+/+ and Tom−/− mice showed significant increases in KCl‐evoked and spontaneous glutamate release in the DG, indicating a correlation with the fully kindled state independent of genotype. Resting glutamate levels in all hippocampal subregions were significantly lower in the kindled Tom−/− mice, suggesting possible changes in basal control of glutamate circuitry in the kindled Tom−/− mice.ConclusionsOur studies demonstrate that increased glutamate release in the hippocampal DG correlates with acceleration of the kindling process. Although STXBP5/tomosyn‐1 loss increased evoked glutamate release in naïve animals contributing to their prokindling phenotype, the kindling process can override any attenuating effect of STXBP5/tomosyn‐1. Loss of this “braking” effect of STXBP5/tomosyn‐1 on kindling progression may set in motion an alternative but ultimately equally ineffective compensatory response, detected here as reduced basal glutamate release.

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“…Cultures derived from synapsin I-or II-knockout mice have functional SV pools of reduced size, and this effect is not rescued by expression of synapsin variants identified in individuals with autism and seizure disorders (43,44). Mutations in syntaxin-binding protein 1 (STXBP1; Munc-18) have been associated with epileptic encephalopathy, intellectual disability, and movement disorders (45)(46)(47), and recently mutations in syntaxin-1B (STX1B) have also been associated with temperature-sensitive seizure disorders (48), indicating that SNARE complex assembly, SV docking, and priming are important steps in the pathway leading to SV fusion (49). Mice lacking the SV protein synaptophysin (SYP) display behavioral deficits consistent with the association between human SYP mutations and intellectual disability (50,51).…”

Section: 7mentioning

confidence: 99%

Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling

Baker¹,

Gordon²,

Grozeva³

et al. 2015

J. Clin. Invest.

106

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Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Cited by 177 publications

References 44 publications

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling

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