Mislocalization of syntaxin‐1 and impaired neurite growth observed in a human iPSC model for STXBP 1 ‐related epileptic encephalopathy
Syntaxin‐binding protein 1 ( STXBP 1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP 1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP 1 haploinsufficiency has not been elucidated. Using pat...
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creator | Yamashita, Satoshi Chiyonobu, Tomohiro Yoshida, Michiko Maeda, Hiroshi Zuiki, Masashi Kidowaki, Satoshi Isoda, Kenichi Morimoto, Masafumi Kato, Mitsuhiro Saitsu, Hirotomo Matsumoto, Naomichi Nakahata, Tatsutoshi Saito, Megumu K. Hosoi, Hajime |
description | Syntaxin‐binding protein 1 (
STXBP
1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene,
STXBP
1,
are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of
STXBP
1
haploinsufficiency has not been elucidated. Using patient‐derived induced pluripotent stem cells (
iPSC
s), we aimed to establish a neuronal model for
STXBP
1
haploinsufficiency and determine the pathophysiologic basis for
STXBP
1
encephalopathy. We generated
iPSC
lines from a patient with Ohtahara syndrome (
OS
) harboring a heterozygous nonsense mutation of
STXBP
1
(c.1099C>T; p.R367X) and performed neuronal differentiation. Both
STXBP
1
messenger RNA (
mRNA
) and
STXBP
1 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
STXBP
1
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
STXBP
1
encephalopathy throughout the stages of neurodevelopment. Reduced expression of
STXBP
1 leads to changes in the expression and localization of syntaxin‐1 that may contribute to the devastating phenotype of
STXBP
1
encephalopathy. |
doi_str_mv | 10.1111/epi.13338 |
format | Article |
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STXBP
1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene,
STXBP
1,
are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of
STXBP
1
haploinsufficiency has not been elucidated. Using patient‐derived induced pluripotent stem cells (
iPSC
s), we aimed to establish a neuronal model for
STXBP
1
haploinsufficiency and determine the pathophysiologic basis for
STXBP
1
encephalopathy. We generated
iPSC
lines from a patient with Ohtahara syndrome (
OS
) harboring a heterozygous nonsense mutation of
STXBP
1
(c.1099C>T; p.R367X) and performed neuronal differentiation. Both
STXBP
1
messenger RNA (
mRNA
) and
STXBP
1 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
STXBP
1
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
STXBP
1
encephalopathy throughout the stages of neurodevelopment. Reduced expression of
STXBP
1 leads to changes in the expression and localization of syntaxin‐1 that may contribute to the devastating phenotype of
STXBP
1
encephalopathy.</description><identifier>ISSN: 0013-9580</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.13338</identifier><language>eng</language><ispartof>Epilepsia (Copenhagen), 2016-04, Vol.57 (4)</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c748-75339dc9469f610670bf1cc0af8bb40ddb5fea54b2ba9c545ea63789c7f5bfb43</citedby><cites>FETCH-LOGICAL-c748-75339dc9469f610670bf1cc0af8bb40ddb5fea54b2ba9c545ea63789c7f5bfb43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Yamashita, Satoshi</creatorcontrib><creatorcontrib>Chiyonobu, Tomohiro</creatorcontrib><creatorcontrib>Yoshida, Michiko</creatorcontrib><creatorcontrib>Maeda, Hiroshi</creatorcontrib><creatorcontrib>Zuiki, Masashi</creatorcontrib><creatorcontrib>Kidowaki, Satoshi</creatorcontrib><creatorcontrib>Isoda, Kenichi</creatorcontrib><creatorcontrib>Morimoto, Masafumi</creatorcontrib><creatorcontrib>Kato, Mitsuhiro</creatorcontrib><creatorcontrib>Saitsu, Hirotomo</creatorcontrib><creatorcontrib>Matsumoto, Naomichi</creatorcontrib><creatorcontrib>Nakahata, Tatsutoshi</creatorcontrib><creatorcontrib>Saito, Megumu K.</creatorcontrib><creatorcontrib>Hosoi, Hajime</creatorcontrib><title>Mislocalization of syntaxin‐1 and impaired neurite growth observed in a human iPSC model for STXBP 1 ‐related epileptic encephalopathy</title><title>Epilepsia (Copenhagen)</title><description>Syntaxin‐binding protein 1 (
STXBP
1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene,
STXBP
1,
are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of
STXBP
1
haploinsufficiency has not been elucidated. Using patient‐derived induced pluripotent stem cells (
iPSC
s), we aimed to establish a neuronal model for
STXBP
1
haploinsufficiency and determine the pathophysiologic basis for
STXBP
1
encephalopathy. We generated
iPSC
lines from a patient with Ohtahara syndrome (
OS
) harboring a heterozygous nonsense mutation of
STXBP
1
(c.1099C>T; p.R367X) and performed neuronal differentiation. Both
STXBP
1
messenger RNA (
mRNA
) and
STXBP
1 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
STXBP
1
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
STXBP
1
encephalopathy throughout the stages of neurodevelopment. Reduced expression of
STXBP
1 leads to changes in the expression and localization of syntaxin‐1 that may contribute to the devastating phenotype of
STXBP
1
encephalopathy.</description><issn>0013-9580</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNotkD1PwzAYhC0EEqUw8A_elSHFruM4GaHiSyoCqR3YoteOTYwSO3JSoEzMTPxGfgnh45aTTqfToyPkmNEZG3VqOjdjnPN8h0yYmOcJY5ncJRNKGU8KkdN9ctD3T5RSmUk-IR-3rm-Cxsa94eCCh2Ch3_oBX53_ev9kgL4C13booqnAm010g4HHGF6GGoLqTXwec-cBod606MHdrxbQhso0YEOE1frh_B4YjFvRNDiM5RGxMd3gNBivTVdjEzoc6u0h2bPY9Obo36dkfXmxXlwny7urm8XZMtEyzRMpOC8qXaRZYTNGM0mVZVpTtLlSKa0qJaxBkaq5wkKLVBjMuMwLLa1QVqV8Sk7-ZnUMfR-NLbvoWozbktHy58NyBCx_P-TfitxpNA</recordid><startdate>201604</startdate><enddate>201604</enddate><creator>Yamashita, Satoshi</creator><creator>Chiyonobu, Tomohiro</creator><creator>Yoshida, Michiko</creator><creator>Maeda, Hiroshi</creator><creator>Zuiki, Masashi</creator><creator>Kidowaki, Satoshi</creator><creator>Isoda, Kenichi</creator><creator>Morimoto, Masafumi</creator><creator>Kato, Mitsuhiro</creator><creator>Saitsu, Hirotomo</creator><creator>Matsumoto, Naomichi</creator><creator>Nakahata, Tatsutoshi</creator><creator>Saito, Megumu K.</creator><creator>Hosoi, Hajime</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>201604</creationdate><title>Mislocalization of syntaxin‐1 and impaired neurite growth observed in a human iPSC model for STXBP 1 ‐related epileptic encephalopathy</title><author>Yamashita, Satoshi ; Chiyonobu, Tomohiro ; Yoshida, Michiko ; Maeda, Hiroshi ; Zuiki, Masashi ; Kidowaki, Satoshi ; Isoda, Kenichi ; Morimoto, Masafumi ; Kato, Mitsuhiro ; Saitsu, Hirotomo ; Matsumoto, Naomichi ; Nakahata, Tatsutoshi ; Saito, Megumu K. ; Hosoi, Hajime</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c748-75339dc9469f610670bf1cc0af8bb40ddb5fea54b2ba9c545ea63789c7f5bfb43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamashita, Satoshi</creatorcontrib><creatorcontrib>Chiyonobu, Tomohiro</creatorcontrib><creatorcontrib>Yoshida, Michiko</creatorcontrib><creatorcontrib>Maeda, Hiroshi</creatorcontrib><creatorcontrib>Zuiki, Masashi</creatorcontrib><creatorcontrib>Kidowaki, Satoshi</creatorcontrib><creatorcontrib>Isoda, Kenichi</creatorcontrib><creatorcontrib>Morimoto, Masafumi</creatorcontrib><creatorcontrib>Kato, Mitsuhiro</creatorcontrib><creatorcontrib>Saitsu, Hirotomo</creatorcontrib><creatorcontrib>Matsumoto, Naomichi</creatorcontrib><creatorcontrib>Nakahata, Tatsutoshi</creatorcontrib><creatorcontrib>Saito, Megumu K.</creatorcontrib><creatorcontrib>Hosoi, Hajime</creatorcontrib><collection>CrossRef</collection><jtitle>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamashita, Satoshi</au><au>Chiyonobu, Tomohiro</au><au>Yoshida, Michiko</au><au>Maeda, Hiroshi</au><au>Zuiki, Masashi</au><au>Kidowaki, Satoshi</au><au>Isoda, Kenichi</au><au>Morimoto, Masafumi</au><au>Kato, Mitsuhiro</au><au>Saitsu, Hirotomo</au><au>Matsumoto, Naomichi</au><au>Nakahata, Tatsutoshi</au><au>Saito, Megumu K.</au><au>Hosoi, Hajime</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mislocalization of syntaxin‐1 and impaired neurite growth observed in a human iPSC model for STXBP 1 ‐related epileptic encephalopathy</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><date>2016-04</date><risdate>2016</risdate><volume>57</volume><issue>4</issue><issn>0013-9580</issn><eissn>1528-1167</eissn><abstract>Syntaxin‐binding protein 1 (
STXBP
1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene,
STXBP
1,
are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of
STXBP
1
haploinsufficiency has not been elucidated. Using patient‐derived induced pluripotent stem cells (
iPSC
s), we aimed to establish a neuronal model for
STXBP
1
haploinsufficiency and determine the pathophysiologic basis for
STXBP
1
encephalopathy. We generated
iPSC
lines from a patient with Ohtahara syndrome (
OS
) harboring a heterozygous nonsense mutation of
STXBP
1
(c.1099C>T; p.R367X) and performed neuronal differentiation. Both
STXBP
1
messenger RNA (
mRNA
) and
STXBP
1 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
STXBP
1
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
STXBP
1
encephalopathy throughout the stages of neurodevelopment. Reduced expression of
STXBP
1 leads to changes in the expression and localization of syntaxin‐1 that may contribute to the devastating phenotype of
STXBP
1
encephalopathy.</abstract><doi>10.1111/epi.13338</doi></addata></record> |
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source | Wiley Free Content; EZB-FREE-00999 freely available EZB journals; Wiley Online Library All Journals; Alma/SFX Local Collection |
title | Mislocalization of syntaxin‐1 and impaired neurite growth observed in a human iPSC model for STXBP 1 ‐related epileptic encephalopathy |
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