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

被引：425

作者：

Saitsu, Hirotomo ^{[1
]}

Kato, Mitsuhiro ^{[2
]}

Mizuguchi, Takeshi ^{[1
]}

Hamada, Keisuke ^{[3
]}

Osaka, Hitoshi ^{[4
]}

Tohyama, Jun ^{[5
]}

Uruno, Katsuhisa ^{[6
]}

Kumada, Satoko ^{[7
]}

Nishiyama, Kiyomi ^{[1
]}

Nishimura, Akira ^{[1
]}

Okada, Ippei ^{[1
]}

Yoshimura, Yukiko ^{[1
]}

Hirai, Syu-ichi ^{[8
]}

Kumada, Tatsuro ^{[9
]}

Hayasaka, Kiyoshi ^{[2
]}

Fukuda, Atsuo ^{[9
]}

Ogata, Kazuhiro ^{[3
]}

Matsumoto, Naomichi ^{[1
]}

机构：

[1] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan

[2] Yamagata Univ, Sch Med, Dept Pediat, Yamagata 9909585, Japan

[3] Yokohama City Univ, Grad Sch Med, Dept Biochem, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan

[4] Kanagawa Childrens Med Ctr, Clin Res Inst, Div Neurol, Minami Ku, Yokohama, Kanagawa 2328555, Japan

[5] Nishi Niigata Chuo Natl Hosp, Dept Pediat, Epilepsy Ctr, Nishi Ku, Niigata 9502085, Japan

[6] Yamagata Natl Hosp, Epilepsy Ctr, Yamagata 9900876, Japan

[7] Tokyo Metropolitan Neurol Hosp, Dept Neuropediat, Fuchu, Tokyo 1830042, Japan

[8] Yokohama City Univ, Grad Sch Med, Dept Mol Biol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan

[9] Hamamatsu Univ Sch Med, Dept Physiol, Hamamatsu, Shizuoka 4313192, Japan

来源：

NATURE GENETICS | 2008年 / 40卷 / 06期

关键词：

D O I：

10.1038/ng.150

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy(1). 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 species(2-4). 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.

引用

页码：782 / 788

页数：7

共 30 条

[1] Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other? [J].