Cortical hyperexcitability, protein instability, and haploinsufficiency are disease mechanisms underlying the disorder STXBP1 encephalopathy with epilepsy, new research from a group in the Netherlands indicates.
STXBP1 encephalopathy with epilepsy is a condition characterized by recurrent seizures (epilepsy), abnormal brain function (encephalopathy), and intellectual disability, including autism spectrum disorders. It is caused by mutations in the STXBP1 gene. This gene provides instructions for making syntaxin-binding protein 1.
In neurons, syntaxin-binding protein 1 helps regulate the release of chemical messengers called neurotransmitters from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function.
Prof. dr. Matthijs Verhage, of the Center for Neurogenomics and Cognitive Research, and colleagues investigated the cellular deficits of seven different STXBP1 mutations. They also developed four mouse models to represent abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy.
“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.”
Early-infantile Epileptic Encephalopathy 4
The signs and symptoms of STXBP1 encephalopathy with epilepsy, also known as early-infantile epileptic encephalopathy 4 (EIEE4), typically begin in infancy but can first appear later in childhood or early adulthood. In many affected individuals, seizures stop in early childhood with the other neurological problems continuing throughout life. However, some people with STXBP1 encephalopathy with epilepsy have seizures that persist.
STXBP1 gene mutations reduce the amount of functional protein produced from the gene, which impairs the release of neurotransmitters from neurons.
A change in neurotransmitter levels can lead to uncontrolled activation (excitation) of neurons, which causes seizures. This altered neuronal activity does not appear to impair the development or survival of neurons; the cause of the encephalopathy and other neurological problems in this condition is unclear.
The work was supported by Agentschap NL, the Netherlands Organization for Scientific Research, and by the European Union ERC Advanced Grant.
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
Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy
Brain, Volume 141, Issue 5, 1 May 2018, Pages 1350–1374, https://doi.org/10.1093/brain/awy046
Abstract and Illustrations © Jovana Kovačević, et al. (2018). Republished via Creative Commons Attribution Non-Commercial License.