Dataset Information

Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy.

ABSTRACT: Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, with the majority affecting postsynaptic apparatuses and much fewer in presynaptic proteins. Syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) is an essential component of the presynaptic neurotransmitter release machinery. De novo heterozygous pathogenic variants in STXBP1 are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, encompass a broad spectrum of neurologic and psychiatric features, but the pathogenesis remains elusive. Here we modeled STXBP1 encephalopathy in mice and found that Stxbp1 haploinsufficiency caused cognitive, psychiatric, and motor dysfunctions, as well as cortical hyperexcitability and seizures. Furthermore, Stxbp1 haploinsufficiency reduced cortical inhibitory neurotransmission via distinct mechanisms from parvalbumin-expressing and somatostatin-expressing interneurons. These results demonstrate that Stxbp1 haploinsufficient mice recapitulate cardinal features of STXBP1 encephalopathy and indicate that GABAergic synaptic dysfunction is likely a crucial contributor to disease pathogenesis.

SUBMITTER: Chen W

PROVIDER: S-EPMC7056272 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy.

Chen Wu W Cai Zhao-Lin ZL Chao Eugene S ES Chen Hongmei H Longley Colleen M CM Hao Shuang S Chao Hsiao-Tuan HT Kim Joo Hyun JH Messier Jessica E JE Zoghbi Huda Y HY Tang Jianrong J Swann John W JW Xue Mingshan M

eLife 20200219

Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, with the majority affecting postsynaptic apparatuses and much fewer in presynaptic proteins. Syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) is an essential component of the presynaptic neurotransmitter release machinery. De novo heterozygous pathogenic variants in STXBP1 are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. Th ...[more]

PMID: 32073399

Similar Datasets

Project description:ObjectiveGenetic variants in STXBP1, which encodes the conserved exocytosis protein Munc18-1, are associated with a variety of infantile epilepsy syndromes. We aimed to develop an in vivo Caenorhabditis elegans model that could be used to test the pathogenicity of such variants in a cost-effective manner.MethodsThe CRISPR/Cas9 method was used to introduce a null mutation into the unc-18 gene (the C. elegans orthologue of STXBP1), thereby creating a paralyzed worm strain. We subsequently rescued this strain with transgenes encoding the human STXBP1/Munc18-1 protein (wild-type and eight different epilepsy-associated missense variants). The resulting humanized worm strains were then analyzed via behavioral, electrophysiological, and biochemical approaches.ResultsTransgenic expression of wild-type human STXBP1 protein fully rescued locomotion in both solid and liquid media to the same level as the standard wild-type worm strain, Bristol N2. Six variant strains (E59K, V84D, C180Y, R292H, L341P, R551C) exhibited impaired locomotion, whereas two (P335L, R406H) were no different from worms expressing wild-type STXBP1. Electrophysiological recordings revealed that all eight variant strains displayed less frequent and more irregular pharyngeal pumping in comparison to wild-type STXBP1-expressing strains. Four strains (V84D, C180Y, R292H, P335L) exhibited pentylenetetrazol-induced convulsions in an acute assay of seizure-like activity, in contrast to worms expressing wild-type STXBP1. No differences were seen between wild-type and variant STXBP1 strains in terms of mRNA abundance. However, STXBP1 protein levels were reduced to 20%-30% of wild-type in all variants, suggesting that the mutations result in STXBP1 protein instability.SignificanceThe approach described here is a cost-effective in vivo method for establishing the pathogenicity of genetic variants in STXBP1 and potentially other conserved neuronal proteins. Furthermore, the humanized strains we created could potentially be used in the future for high-throughput drug screens to identify novel therapeutics.

Project description:Objective STXBP1 mutations are associated with early onset epileptic encephalopathy (EOEE). Our aim was to explore the phenotype spectrum, clinical treatment and prognosis of STXBP1-related encephalopathy (STXBP1-E). Methods Clinical and genetic data were collected from 10 patients with STXBP1 mutations. These patients were examined and diagnosed from 2015 to 2021 at the Pediatric Department of Qilu Hospital. Blood samples were collected and sequenced by next generation sequencing and Candidate pathogenic variants were identified using Sanger sequencing in all family members. Results All of the patients showed severe epilepsy, varying degrees of intellectual disability and delayed motor. The patients developed multiple seizure types and abnormal electroencephalography (EEG) results at onset, and focal seizures were the most frequent seizure type. Among the patients, 2 were diagnosed with Ohtahara syndrome, 2 patient was diagnosed with West syndrome. The other 6 patients could not be diagnosed with any specifically recognized epilepsy syndrome. Five of the 10 patients had a history of fever with seizures, 4 of whom had eliminated intracranial infection according to the results of cerebrospinal fluid (CSF) examinations, and the other patient was diagnosed with anti-myelin oligodendrocyte glycoprotein (MOG) -associated encephalitis. We identified one patient with a complete deletion of STXBP1 and 9 patients with de novo heterozygous mutations of STXBP1. Among those mutations, 4 were novel (c.56°C > T, c.1315A > T, c.751G > C, and c.554_559del), and 5 had been previously reported [c.364C > T, c.569G > A (2 cases), c.748C > T, and c.1651C > T]. For 8 of our patients, different combinations of anti-seizure medications (ASMs) led to seizure freedom. One patient with MOG antibodies in his serum obtained a poor therapeutic effect from the traditional ASMs treatment, so he had to achieve seizure-free status through vagus nerve stimulation (VNS), which had little effect on his psychomotor ability. Fortunately, in one case, patient psychomotor ability was improved through VNS. Conclusion Our study shows that STXBP1 screening should be considered in patients with neonatal seizures with intellectual disability, and frequent seizures with fever should also be considered with the STXBP1 mutation when intracranial infection is eliminated. VNS has expanded outcome measures to include behavioral and developmental function as well as seizure control.

Dataset Information

Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy.

Publications

<i>Stxbp1/Munc18-1</i> haploinsufficiency impairs inhibition and mediates key neurological features of <i>STXBP1</i> encephalopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets