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 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.
Saitsu
Hirotomo
H
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>
Kato
Mitsuhiro
M
Mizuguchi
Takeshi
T
Hamada
Keisuke
K
Osaka
Hitoshi
H
Tohyama
Jun
J
Uruno
Katsuhisa
K
Kumada
Satoko
S
Nishiyama
Kiyomi
K
Nishimura
Akira
A
Okada
Ippei
I
Yoshimura
Yukiko
Y
Hirai
Syu-ichi
S
Kumada
Tatsuro
T
Hayasaka
Kiyoshi
K
Fukuda
Atsuo
A
Ogata
Kazuhiro
K
Matsumoto
Naomichi
N
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
D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; C497937:STXBP1 protein, human