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Brain. 2018 May 1;141(5):1350-1374. doi: 10.1093/brain/awy046.

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

Author information

1
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam and VU Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
2
Sylics (Synaptologics BV), Amsterdam, The Netherlands.
3
Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam and VU Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
4
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam and VU Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
5
Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany.
6
UNC Center for Psychiatric Genomics, University of North Carolina at Chapel Hill, 101 Manning Drive, Chapel Hill, NC 27599-7160, USA.
7
Karolinska Institutet, Department of Medical Epidemiology and Biostatistics and Department of (Clinical) Genetics, Nobels väg 12A, 171 77 Stockholm, Sweden.

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.

PMID:
29538625
PMCID:
PMC5917748
DOI:
10.1093/brain/awy046
[Indexed for MEDLINE]
Free PMC Article

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