Abstract
Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy1. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3–q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species2,3,4. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ohtahara, S. et al. On the specific age dependent epileptic syndrome: the early-infantile epileptic encephalopathy with suppression-burst [in Japanese with English abstract]. No To Hattatsu 8, 270–279 (1976).
Verhage, M. et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 864–869 (2000).
Harrison, S.D., Broadie, K., van de Goor, J. & Rubin, G.M. Mutations in the Drosophila Rop gene suggest a function in general secretion and synaptic transmission. Neuron 13, 555–566 (1994).
Weimer, R.M. et al. Defects in synaptic vesicle docking in unc-18 mutants. Nat. Neurosci. 6, 1023–1030 (2003).
Djukic, A., Lado, F.A., Shinnar, S. & Moshe, S.L. Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other? Epilepsy Res. 70 (suppl. 1), S68–S76 (2006).
Ohtahara, S. & Yamatogi, Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res. 70, S58–S67 (2006).
Kato, M., Das, S., Petras, K., Sawaishi, Y. & Dobyns, W.B. Polyalanine expansion of ARX associated with cryptogenic West syndrome. Neurology 61, 267–276 (2003).
Kato, M. et al. A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). Am. J. Hum. Genet. 81, 361–366 (2007).
Vissers, L.E.L.M., Veltman, J.A., van Kessel, A.G. & Brunner, H.G. Identification of disease genes by whole genome CGH arrays. Hum. Mol. Genet. 14, R215–R223 (2005).
Feuk, L., Marshall, C.R., Wintle, R.F. & Scherer, S.W. Structural variants: changing the landscape of chromosomes and design of disease studies. Hum. Mol. Genet. 15, R57–R66 (2006).
Garcia, E.P., Gatti, E., Butler, M., Burton, J. & De Camilli, P. A rat brain Sec1 homologue related to Rop and UNC18 interacts with syntaxin. Proc. Natl. Acad. Sci. USA 91, 2003–2007 (1994).
Kalidas, S. et al. Expression of p67 (Munc-18) in adult human brain and neuroectodermal tumors of human central nervous system. Acta Neuropathol. 99, 191–198 (2000).
Tohyama, J. et al. Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter. Brain Dev. 30, 349–355 (2008).
Misura, K.M.S., Scheller, R.H. & Weis, W.I. Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex. Nature 404, 355–362 (2000).
Yang, J.T., Wu, C.S. & Martinez, H.M. Calculation of protein conformation from circular dichroism. Methods Enzymol. 130, 208–269 (1986).
Dulubova, I. et al. Munc18–1 binds directly to the neuronal SNARE complex. Proc. Natl. Acad. Sci. USA 104, 2697–2702 (2007).
Toonen, R.F. & Verhage, M. Munc18–1 in secretion: lonely Munc joins SNARE team and takes control. Trends Neurosci. 30, 564–572 (2007).
Rickman, C., Medine, C.N., Bergmann, A. & Duncan, R.R. Functionally and spatially distinct modes of munc18-syntaxin 1 interaction. J. Biol. Chem. 282, 12097–12103 (2007).
Shen, J., Tareste, D.C., Paumet, F., Rothman, J.E. & Melia, T.J. Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell 128, 183–195 (2007).
Weimer, R.M. & Richmond, J.E. Synaptic vesicle docking: a putative role for the Munc18/Sec1 protein family. Curr. Top. Dev. Biol. 65, 83–113 (2005).
Sudhof, T.C. The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547 (2004).
Rizo, J. & Sudhof, T.C. Snares and Munc18 in synaptic vesicle fusion. Nat. Rev. Neurosci. 3, 641–653 (2002).
Hata, Y., Slaughter, C.A. & Sudhof, T.C. Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 366, 347–351 (1993).
Gurnett, C.A. & Hedera, P. New ideas in epilepsy genetics: novel epilepsy genes, copy number alterations, and gene regulation. Arch. Neurol. 64, 324–328 (2007).
Garcia, C.C. et al. Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. J. Med. Genet. 41, 183–186 (2004).
Toonen, R.F. et al. Munc18–1 expression levels control synapse recovery by regulating readily releasable pool size. Proc. Natl. Acad. Sci. USA 103, 18332–18337 (2006).
Spreafico, R. et al. Burst suppression and impairment of neocortical ontogenesis: electroclinical and neuropathologic findings in two infants with early myoclonic encephalopathy. Epilepsia 34, 800–808 (1993).
Harada, N. et al. Subtelomere specific microarray based comparative genomic hybridisation: a rapid detection system for cryptic rearrangements in idiopathic mental retardation. J. Med. Genet. 41, 130–136 (2004).
Miyake, N. et al. BAC array CGH reveals genomic aberrations in idiopathic mental retardation. Am. J. Med. Genet. A. 140, 205–211 (2006).
Dulubova, I. et al. A conformational switch in syntaxin during exocytosis: role of munc18. EMBO J. 18, 4372–4382 (1999).
Acknowledgements
We thank subjects and their families for their participation in this study. This work was supported by Research Grants from the Ministry of Health, Labour and Welfare (N.M.) and a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (N.M.).
Author information
Authors and Affiliations
Corresponding authors
Supplementary information
Supplementary Text and Figures
Supplementary Notes, Supplementary Methods, Supplementary Figure 1 and Supplementary Table 1 (PDF 1210 kb)
Supplementary Video 1
Tonic spasms in series were observed, consisting of a sudden brief extension of the neck, trunk, and extremities, immediately followed by a bilateral flexion of the extremities with a twist of the trunk, in patient 7 at age two months (MOV 4235 kb)
Rights and permissions
About this article
Cite this article
Saitsu, H., Kato, M., Mizuguchi, T. et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 40, 782–788 (2008). https://doi.org/10.1038/ng.150
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.150
This article is cited by
-
The effect of psychoactive bacteria, Bifidobacterium longum Rosell®-175 and Lactobacillus rhamnosus JB-1, on brain proteome profiles in mice
Psychopharmacology (2024)
-
HSV-1 latency-associated transcript miR-H3 and miR-H4 target STXBP1 and GABBR2 genes
Journal of NeuroVirology (2023)
-
Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants
Genome Medicine (2022)
-
Calcium channelopathies and intellectual disability: a systematic review
Orphanet Journal of Rare Diseases (2021)
-
mTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation
Nature Communications (2021)