title: 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 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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. hsaitsu@yokohama-cu.ac.jp <hsaitsu@yokohama-cu.ac.jp>
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Uruno
authors.forename: Satoko
authors.initials: S
authors.lastname: Kumada
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Akira
authors.initials: A
authors.lastname: Nishimura
authors.forename: Ippei
authors.initials: I
authors.lastname: Okada
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Syu-ichi
authors.initials: S
authors.lastname: Hirai
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kumada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000000981:diagnostic imaging; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D002942:Circular Dichroism; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology; D005260:Female; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D051938:Munc18 Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009693:Nucleic Acid Hybridization; D011487:Protein Conformation; D050765:Qa-SNARE Proteins / Q000378:metabolism; D011859:Radiography; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; C497937:STXBP1 protein, human