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

• DOI: 10.1038/ng.150
• Publication Date: 2008-05-11T18:43:50Z
• Authors: Hirotomo Saitsu; Mitsuhiro Kato; Takeshi Mizuguchi; Keisuke Hamada; Hitoshi Osaka; Jun Tohyama; Katsuhisa Uruno; Satoko Kumada; Kiyomi Nishiyama; Akira Nishimura; Ippei Okada; Yukiko Yoshimura; Syu-ichi Hirai; Tatsuro Kumada; Kiyoshi Hayasaka; Atsuo Fukuda; Kazuhiro Ogata; Naomichi Matsumoto
• Keywords: Adult; Male; Heterozygote; Genome, Human; Circular Dichroism; Molecular Sequence Data; Infant, Newborn; Brain; Infant; Electroencephalography; Epilepsies, Myoclonic; Microarray Analysis; Magnetic Resonance Imaging; 03 medical and health sciences; Munc18 Proteins; 0302 clinical medicine; Humans; Female; Amino Acid Sequence; Chromosome Deletion; Chromosomes, Human, Pair 9; In Situ Hybridization, Fluorescence

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