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

Nature Genetics volume 40, pages 782–788 (2008)Cite this article

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.

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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.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

Protein Data Bank

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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.).

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Authors and Affiliations

  1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004, Yokohama, Japan

    Hirotomo Saitsu, Takeshi Mizuguchi, Kiyomi Nishiyama, Akira Nishimura, Ippei Okada, Yukiko Yoshimura & Naomichi Matsumoto

  2. Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan

    Mitsuhiro Kato & Kiyoshi Hayasaka

  3. Department of Biochemistry, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004, Yokohama, Japan

    Keisuke Hamada & Kazuhiro Ogata

  4. Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ku, 232-8555, Yokohama, Japan

    Hitoshi Osaka

  5. Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, 1-14-1 Masago, Nishi-ku, 950-2085, Niigata, Japan

    Jun Tohyama

  6. Epilepsy Center, Yamagata National Hospital, 126-2 Gyosai, Yamagata, 990-0876, Japan

    Katsuhisa Uruno

  7. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai, Fuchu, 183-0042, Japan

    Satoko Kumada

  8. Department of Molecular Biology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004, Yokohama, Japan

    Syu-ichi Hirai

  9. Department of Physiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Tatsuro Kumada & Atsuo Fukuda

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  1. Hirotomo Saitsu
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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)

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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

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