Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: A 2.0-Mb microdeletion at 9q33.3–q34.11 involving STXBP1 in an individual with EIEE.
Figure 2: Heterozygous mutations of STXBP1 found in individuals with EIEE.
Figure 3: Brain MRI and EEG of subjects with EIEE having STXBP1 defects.
Figure 4: Structural and functional characterization of STXBP1 mutant proteins.

Accession codes

Accessions

GenBank/EMBL/DDBJ

Gene Expression Omnibus

Protein Data Bank

References

  1. 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).

    Google Scholar 

  2. Verhage, M. et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 864–869 (2000).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Weimer, R.M. et al. Defects in synaptic vesicle docking in unc-18 mutants. Nat. Neurosci. 6, 1023–1030 (2003).

    Article  CAS  Google Scholar 

  5. 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).

    Article  Google Scholar 

  6. 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).

    Article  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Tohyama, J. et al. Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter. Brain Dev. 30, 349–355 (2008).

    Article  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Yang, J.T., Wu, C.S. & Martinez, H.M. Calculation of protein conformation from circular dichroism. Methods Enzymol. 130, 208–269 (1986).

    Article  CAS  Google Scholar 

  16. Dulubova, I. et al. Munc18–1 binds directly to the neuronal SNARE complex. Proc. Natl. Acad. Sci. USA 104, 2697–2702 (2007).

    Article  CAS  Google Scholar 

  17. Toonen, R.F. & Verhage, M. Munc18–1 in secretion: lonely Munc joins SNARE team and takes control. Trends Neurosci. 30, 564–572 (2007).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. Sudhof, T.C. The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547 (2004).

    Article  Google Scholar 

  22. Rizo, J. & Sudhof, T.C. Snares and Munc18 in synaptic vesicle fusion. Nat. Rev. Neurosci. 3, 641–653 (2002).

    Article  CAS  Google Scholar 

  23. Hata, Y., Slaughter, C.A. & Sudhof, T.C. Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 366, 347–351 (1993).

    Article  CAS  Google Scholar 

  24. 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).

    Article  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Miyake, N. et al. BAC array CGH reveals genomic aberrations in idiopathic mental retardation. Am. J. Med. Genet. A. 140, 205–211 (2006).

    Article  Google Scholar 

  30. Dulubova, I. et al. A conformational switch in syntaxin during exocytosis: role of munc18. EMBO J. 18, 4372–4382 (1999).

    Article  CAS  Google Scholar 

Download references

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

Authors

Corresponding authors

Correspondence to Hirotomo Saitsu or Naomichi Matsumoto.

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

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.150

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing