| Item type |
itemtype_ver1(1) |
| 公開日 |
2022-10-14 |
| タイトル |
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タイトル |
VWF‐Gly2752Ser, a novel non‐cysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering C‐terminal dimer formation |
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言語 |
en |
| 著者 |
Okamoto, Shuichi
Tamura, Shogo
Sanda, Naomi
Odaira, Koya
Hayakawa, Yuri
Mukaide, Masato
Suzuki, Atsuo
Kanematsu, Takeshi
Hayakawa, Fumihiko
Katsumi, Akira
Kiyoi, Hitoshi
Kojima, Tetsuhito
Matsushita, Tadashi
Suzuki, Nobuaki
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| アクセス権 |
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アクセス権 |
open access |
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アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 権利 |
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言語 |
en |
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権利情報 |
"This is the peer reviewed version of the following article: [Okamoto, S, Tamura, S, Sanda, N, et al. VWF-Gly2752Ser, a novel non-cysteine substitution variant in the CK domain, exhibits severe secretory impairment by hampering C-terminal dimer formation. J Thromb Haemost. 2022; 20: 1784–1796. https://doi.org/10.1111/jth.15746], which has been published in final form at [https://doi.org/10.1111/jth.15746]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited." |
| 内容記述 |
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内容記述タイプ |
Abstract |
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内容記述 |
Background: Von Willebrand factor (VWF) is a multimeric glycoprotein that plays important roles in hemostasis and thrombosis. C-terminal interchain-disulfide bonds in the cystine knot (CK) domain are essential for VWF dimerization. Previous studies have reported that missense variants of cysteine in the CK domain disrupt the intrachain-disulfide bond and cause type 3 von Willebrand disease (VWD). However, type 3 VWD-associated noncysteine substitution variants in the CK domain have not been reported. Objective: To investigate the molecular mechanism of a novel non-cysteine variant in the CK domain, VWF c.8254 G>A (p.Gly2752Ser), which was identified in a patient with type 3 VWD as homozygous. Methods: Genetic analysis was performed by whole exome sequencing and Sanger sequencing. VWF multimer analysis was performed using SDS-agarose electrophoresis. VWF production and subcellular localization were analyzed using ex vivo endothelial colony forming cells (ECFCs) and an in vitro recombinant VWF (rVWF) expression system. Results: The patient was homozygous for VWF-Gly2752Ser. Plasma VWF enzyme-linked immunosorbent assay showed that the VWF antigen level of the patient was 1.2% compared with healthy subjects. A tiny amount of VWF was identified in the patient's ECFC. Multimer analysis revealed that the circulating VWF-Gly2752Ser presented only low molecular weight multimers. Subcellular localization analysis of VWF-Gly2752Ser-transfected cell lines showed that rVWF-Gly2752Ser was severely impaired in its ER-to-Golgi trafficking. Conclusion: VWF-Gly2752Ser causes severe secretory impairment because of its dimerization failure. This is the first report of a VWF variant with a noncysteine substitution in the CK domain that causes type 3 VWD. |
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言語 |
en |
| 出版者 |
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出版者 |
Wiley |
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言語 |
en |
| 言語 |
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言語 |
eng |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 出版タイプ |
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出版タイプ |
AM |
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出版タイプResource |
http://purl.org/coar/version/c_ab4af688f83e57aa |
| 関連情報 |
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関連タイプ |
isVersionOf |
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識別子タイプ |
DOI |
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関連識別子 |
https://doi.org/10.1111/jth.15746 |
| 収録物識別子 |
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収録物識別子タイプ |
PISSN |
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収録物識別子 |
1538-7933 |
| 書誌情報 |
en : Journal of Thrombosis and Haemostasis
巻 20,
号 8,
p. 1784-1796,
発行日 2022-08
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| ファイル公開日 |
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日付 |
2023-08-01 |
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日付タイプ |
Available |
J_of_Thrombosis_Haemost_2022_Okamoto_VWF_Gly2752Ser.pdf (19.2 MB)
