Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy

Jovana Kovačević, Gregoire Maroteaux, Desiree Schut, Maarten Loos, Mohit Dubey, Julika Pitsch, Esther Remmelink, Bastijn Koopmans, James Crowley, L. Niels Cornelisse, Patrick F. Sullivan, Susanne Schoch, Ruud F. Toonen, Oliver Stiedl, Matthijs Verhage

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background. All disease variants had severely decreased protein levels. Together, these cellular studies suggest that impaired protein stability and STXBP1 haploinsufficiency explain STXBP1-encephalopathy and that, therefore, Stxbp1 +/- mice provide a valid mouse model. Simultaneous video and EEG recordings revealed that Stxbp1 +/- mice with different genomic backgrounds recapitulate the seizure/spasm phenotype observed in humans, characterized by myoclonic jerks and spike-wave discharges that were suppressed by the antiepileptic drug levetiracetam. Mice heterozygous for Stxbp1 in GABAergic neurons only, showed impaired viability, 50% died within 2-3 weeks, and the rest showed stronger epileptic activity. c-Fos staining implicated neocortical areas, but not other brain regions, as the seizure foci. Stxbp1 +/- mice showed impaired cognitive performance, hyperactivity and anxiety-like behaviour, without altered social behaviour. Taken together, these data demonstrate the construct, face and predictive validity of Stxbp1 +/- mice and point to protein instability, haploinsufficiency and imbalanced excitation in neocortex, as the underlying mechanism of STXBP1-encephalopathy. The mouse models reported here are valid models for development of therapeutic interventions targeting STXBP1-encephalopathy.

Original languageEnglish
Pages (from-to)1350-1374
Number of pages25
JournalBrain
Volume141
Issue number5
Early online date12 Mar 2018
DOIs
Publication statusPublished - 1 May 2018

Fingerprint

Haploinsufficiency
Brain Diseases
Proteins
etiracetam
Electroencephalography
Seizures
Genetic Databases
GABAergic Neurons
Video Recording
Mutation
Myoclonus
Cortical Excitability
Protein Stability
Social Behavior
Neocortex
Spasm
Reproducibility of Results
Synaptic Transmission
Intellectual Disability
Anticonvulsants

Keywords

  • behavioural inflexibility
  • epilepsy
  • haploinsufficiency
  • STXBP1-encephalopathy
  • video-EEG

Cite this

Kovačević, Jovana ; Maroteaux, Gregoire ; Schut, Desiree ; Loos, Maarten ; Dubey, Mohit ; Pitsch, Julika ; Remmelink, Esther ; Koopmans, Bastijn ; Crowley, James ; Cornelisse, L. Niels ; Sullivan, Patrick F. ; Schoch, Susanne ; Toonen, Ruud F. ; Stiedl, Oliver ; Verhage, Matthijs. / Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy. In: Brain. 2018 ; Vol. 141, No. 5. pp. 1350-1374.
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abstract = "De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background. All disease variants had severely decreased protein levels. Together, these cellular studies suggest that impaired protein stability and STXBP1 haploinsufficiency explain STXBP1-encephalopathy and that, therefore, Stxbp1 +/- mice provide a valid mouse model. Simultaneous video and EEG recordings revealed that Stxbp1 +/- mice with different genomic backgrounds recapitulate the seizure/spasm phenotype observed in humans, characterized by myoclonic jerks and spike-wave discharges that were suppressed by the antiepileptic drug levetiracetam. Mice heterozygous for Stxbp1 in GABAergic neurons only, showed impaired viability, 50{\%} died within 2-3 weeks, and the rest showed stronger epileptic activity. c-Fos staining implicated neocortical areas, but not other brain regions, as the seizure foci. Stxbp1 +/- mice showed impaired cognitive performance, hyperactivity and anxiety-like behaviour, without altered social behaviour. Taken together, these data demonstrate the construct, face and predictive validity of Stxbp1 +/- mice and point to protein instability, haploinsufficiency and imbalanced excitation in neocortex, as the underlying mechanism of STXBP1-encephalopathy. The mouse models reported here are valid models for development of therapeutic interventions targeting STXBP1-encephalopathy.",
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Kovačević, J, Maroteaux, G, Schut, D, Loos, M, Dubey, M, Pitsch, J, Remmelink, E, Koopmans, B, Crowley, J, Cornelisse, LN, Sullivan, PF, Schoch, S, Toonen, RF, Stiedl, O & Verhage, M 2018, 'Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy' Brain, vol. 141, no. 5, pp. 1350-1374. https://doi.org/10.1093/brain/awy046

Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy. / Kovačević, Jovana; Maroteaux, Gregoire; Schut, Desiree; Loos, Maarten; Dubey, Mohit; Pitsch, Julika; Remmelink, Esther; Koopmans, Bastijn; Crowley, James; Cornelisse, L. Niels; Sullivan, Patrick F.; Schoch, Susanne; Toonen, Ruud F.; Stiedl, Oliver; Verhage, Matthijs.

In: Brain, Vol. 141, No. 5, 01.05.2018, p. 1350-1374.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Kovačević, Jovana

AU - Maroteaux, Gregoire

AU - Schut, Desiree

AU - Loos, Maarten

AU - Dubey, Mohit

AU - Pitsch, Julika

AU - Remmelink, Esther

AU - Koopmans, Bastijn

AU - Crowley, James

AU - Cornelisse, L. Niels

AU - Sullivan, Patrick F.

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AU - Toonen, Ruud F.

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