• Satoshi Yamashita, Tomohiro Chiyonobu, Michiko Yoshida, Hiroshi Maeda, Masashi Zuiki, Satoshi Kidowaki, Kenichi Isoda, Masafumi Morimoto, Mitsuhiro Kato, Hirotomo Saitsu, Naomichi Matsumoto, Tatsutoshi Nakahata, Megumu K Saito, and Hajime Hosoi.
• Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
• Epilepsia. 2016 Apr 1; 57 (4): e81-6.

AbstractSyntaxin-binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient-derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS-derived neurons were approximately 50% lower than that of control-derived neurons, suggesting that OS-derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS-derived neurons show reduced levels and mislocalization of syntaxin-1, a component of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. In addition, OS-derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin-1 that may contribute to the devastating phenotype of STXBP1 encephalopathy. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

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