title: STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.
abstract: OBJECTIVE
  De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects.
  
  
  METHODS
  STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells.
  
  
  RESULTS
  A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells.
  
  
  CONCLUSIONS
  Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan. 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: Ippei
authors.initials: I
authors.lastname: Okada
authors.forename: Kenji E
authors.initials: KE
authors.lastname: Orii
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Higuchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Hoshino
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tagawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kimura
authors.forename: Akira
authors.initials: A
authors.lastname: Sudo
authors.forename: Sahoko
authors.initials: S
authors.lastname: Miyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takami
authors.forename: Toshihide
authors.initials: T
authors.lastname: Watanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Nishimura
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Takahito
authors.initials: T
authors.lastname: Wada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Naomi
authors.initials: N
authors.lastname: Kondo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D001921:Brain / Q000503:physiopathology; D004569:Electroencephalography / Q000706:statistics & numerical data*; D004829:Epilepsy, Generalized / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051938:Munc18 Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics* / Q000502:physiology; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology
chemical_list: D051938:Munc18 Proteins; C497937:STXBP1 protein, human