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


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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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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Correspondence to Hirotomo Saitsu or Naomichi Matsumoto.

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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).

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