STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.
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.
Saitsu
Hirotomo
H
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan. hsaitsu@yokohama-cu.ac.jp
Kato
Mitsuhiro
M
Okada
Ippei
I
Orii
Kenji E
KE
Higuchi
Tsukasa
T
Hoshino
Hideki
H
Kubota
Masaya
M
Arai
Hiroshi
H
Tagawa
Tetsuzo
T
Kimura
Shigeru
S
Sudo
Akira
A
Miyama
Sahoko
S
Takami
Yuichi
Y
Watanabe
Toshihide
T
Nishimura
Akira
A
Nishiyama
Kiyomi
K
Miyake
Noriko
N
Wada
Takahito
T
Osaka
Hitoshi
H
Kondo
Naomi
N
Hayasaka
Kiyoshi
K
Matsumoto
Naomichi
N
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
D051938:Munc18 Proteins; C497937:STXBP1 protein, human