De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy

Saitsu, Hirotomo; Kato, Mitsuhiro; Mizuguchi, Takeshi; Hamada, Keisuke; Osaka, Hitoshi; Tohyama, Jun; Uruno, Katsuhisa; Kumada, Satoko; Nishiyama, Kiyomi; Nishimura, Akira; Okada, Ippei; Yoshimura, Yukiko; Hirai, Syu-ichi; Kumada, Tatsuro; Hayasaka, Kiyoshi; Fukuda, Atsuo; Ogata, Kazuhiro; Matsumoto, Naomichi

doi:10.1038/ng.150

Cited by 496 publications

(496 citation statements)

References 29 publications

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“…All the variants were confirmed as de novo by Sanger sequencing, and were predicted to be damaging by Web‐based prediction tools, and not found in ExAC (http://exac.broadinstitute.org) and gnomAD database (http://gnomad.broadinstitute.org/) (Table S1). Parentage was confirmed by microsatellite analysis as previously described 24. We confirmed that c.817‐1G>A causes skipping of exon 11 leading to in‐frame deletion (p.His273_Lys300del) and other two minor abnormal splicing resulting in frameshift using minigene assay (Fig.…”

Section: Resultssupporting

confidence: 71%

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

Akita

Aoto

Kato

et al. 2018

Ann Clin Transl Neurol

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Objective α (CAMK2A) and β (CAMK2B) isoforms of Calcium/calmodulin‐dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α‐ and β‐CaMKII variants in neurodevelopmental disorders.MethodsWhole‐exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis.ResultsWe identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in‐frame deletion of the regulatory segment of CaMKII α. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro‐2a neuroblastoma cells. Expression of a CaMKII α mutant in primary hippocampal neurons significantly increased A‐type K+ currents, which facilitated spike repolarization of single action potentials.InterpretationOur data highlight the importance of CaMKII α and CaMKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A‐type K+ currents as a possible pathophysiological basis.

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Section: Resultssupporting

confidence: 71%

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

Akita

Aoto

Kato

et al. 2018

Ann Clin Transl Neurol

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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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“…8 Biological parentage was judged if more than four informative markers were compatible and other uninformative markers showed no discrepancies.…”

Section: Parentage Testingmentioning

confidence: 99%

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

Yoneda

Saitsu

Touyama³

et al. 2012

J Hum Genet

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Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T4C (p.Leu60Pro) mutation occurred de novo and the c.362G4C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

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De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy

Cited by 496 publications

References 29 publications

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

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

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

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