Analysis of Chst14 gene-deleted mice as a model of Musculocontractural Ehlers-Danlos syndrome

• Project/Area Number: 16K19396
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Shinshu University
• Principal Investigator: Yoshizawa Takahiro 信州大学, 学術研究院総合人間科学系, 助教 (40713392)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 疾患モデル動物 / 筋拘縮型エーラス・ダンロス症候群(mcEDS) / Chst14遺伝子欠損マウス / エーラスダンロス症候群 / 血管異常 / 新型エーラスダンロス症候群 / 遺伝子組換えマウス / 病態メカニズム解析

Outline of Final Research Achievements

Musculocontractural Ehlers-Danlos Syndrome (mcEDS) is a new type of EDS caused by a defect of dermatan 4-O-sulfotransferase-1 resulting from mutations in carbohydrate sulfotransferase 14 gene (CHST14). This disorder is characterized by multiple congenital malformations and progressive multisystem fragility-related complications.
Chst14 gene-deleted mice (KO) were expected to be an animal model of mcEDS. However, most Chst14 homozygous KO (Chst14-/-) mice died in utero. First, we investigated embryo and placenta of Chst14-/-. The placenta of Chst14-/- fetal mice showed alterations in vascular structure and ischemic changes. Next, we found that backcrossing of the mice to BALB/c strain improved birth rate of Chst14-/-.

Academic Significance and Societal Importance of the Research Achievements

mcEDSは近年報告された新しいタイプの疾患であり、病態メカニズムの解明や治療法の開発が急務である。そのためには、疾患モデル動物が必要であるため、本研究ではChst14 KOマウスを用いた検討を行った。その結果、Chst14が胎盤絨毛の毛細血管基底膜の構造維持に重要であることが明らかになり、mcEDSの血管合併症との関連が示唆された。また、従来のChst14 KOマウスは出生率が低く成獣での解析が困難であったが、本研究によって出生率改善方法が確立された。以上の研究成果は、mcEDSの病態メカニズム解明の糸口になるだけでなく、今後のmcEDS研究発展への寄与が期待される。

Research Products

• [Journal Article] Backcrossing to an Appropriate Genetic Background Improves the Birth Rate of Carbohydrate Sulfotransferase 14 Gene-deleted Mice (2020)
  • Author(s): Shin Shimada, Takahiro Yoshizawa, Yuki Takahashi, Yuko Nitahara-Kasahara, Takashi Okada, Yoshihiro Nomura, Hitoki Yamanaka, Tomoki Kosho, Kiyoshi Matsumoto
  • Journal Title: Experimental Animals Volume: -
  • NAID: 130007938664
  • Peer Reviewed / Open Access
• [Journal Article] Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome (2019)
  • Author(s): Tomoki Kosho, Shuji Mizumoto, Takafumi Watanabe, Takahiro Yoshizawa, Noriko Miyake, Shuhei Yamada
  • Journal Title: Genes Volume: 11 Issue: 1 Pages: 43-43
  • DOI: 10.3390/genes11010043
  • NAID: 120006901092
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular abnormalities in the placenta of Chst14-/- fetuses: implications in the pathophysiology of perinatal lethality of the murine model and vascular lesions in human CHST14/D4ST1 deficiency (2018)
  • Author(s): Takahiro Yoshizawa, Shuji Mizumoto, Yuki Takahashi, Shin Shimada, Kazuyuki Sugahara, Jun Nakayama, Shin’ichi Takeda, Yoshihiro Nomura, Yuko Nitahara-Kasahara, Takashi Okada, Kiyoshi Matsumoto, Shuhei Yamada, and Tomoki Kosho
  • Journal Title: Glycobiology Volume: 28 Issue: 2 Pages: 80-89
  • DOI: 10.1093/glycob/cwx099
  • Peer Reviewed
• [Presentation] Skin and Vascular Abnormalities in Chst14 Gene-Deleted Mice, an Animal Model of Musculocontractual Ehlers-Danlos Syndrome (2019)
  • Author(s): Takahiro Yoshizawa, Shuji Mizumoto, Yuki Takahashi, Shin Shimada, Kazuyuki Sugahara, Jun Nakayama, Shin’ichi Takeda, Yoshihiro Nomura, Yuko Nitahara-Kasahara, Takashi Okada, Kiyoshi Matsumoto, Shuhei Yamada, Tomoki Kosho
  • Organizer: The Ehlers-Danlos Society , Scientific Meeting on the Rarer Types of Ehlers-Danlos Syndromes 2019
  • Int'l Joint Research
• [Presentation] Chst14遺伝子欠損マウスを用いた筋拘縮型エーラスダンロス症候群(mcEDS)の血管・皮膚症状の病態解析(Skin and Vascular Abnormalities in Chst14 Knockout Mice, an Animal Model of Musculocontractural Ehlers-Danlos Syndrome) (2019)
  • Author(s): 吉沢隆浩、嶋田新、高橋有希、水本秀二、山田修平、古庄知己
  • Organizer: 日本人類遺伝学会 , 日本人類遺伝学会第64回大会
• [Presentation] Pathophysiological investigation of Musculocontractural Ehlers-Danlos Syndrome caused by mutations in CHST14 (mcEDS-CHST14) using knockout mice (2018)
  • Author(s): Takahiro Yoshizawa, Shuji Mizumoto, Yuki Takahashi, Shin Shimada, Kazuyuki Sugahara, Jun Nakayama, Shin’ichi Takeda, Yoshihiro Nomura, Yuko Nitahara-Kasahara, Takashi Okada, Kiyoshi Matsumoto, Shuhei Yamada, Tomoki Kosho
  • Organizer: International Symposium on the Ehlers-Danlos Syndromes 2018
  • Int'l Joint Research
• [Presentation] Chst14遺伝子欠損マウスの出生率改善方法の検討 (2018)
  • Author(s): 嶋田 新、吉沢 隆浩、山中 仁木、古庄 知己、松本 清司
  • Organizer: 第65回日本実験動物学会総会
• [Presentation] 遺伝背景の違いによるChst14遺伝子欠損マウスの出生率の違い (2018)
  • Author(s): 嶋田 新、吉沢 隆浩、松本 清司
  • Organizer: 信州実験動物研究会
• [Presentation] Pathophysiological investigation of Ehlers-Danlos syndorome caused by CHST14/D4ST1 deficiency using iPS cell and knockout mice (2016)
  • Author(s): Tomoki Kosho, Nana Tsumita, Chiaki Masuda, Takahiro Yoshizawa, et al.
  • Organizer: The 13th International Congress of Human Genetics (ICHG2016)
  • Place of Presentation: 京都国際会館, 京都市, 京都府
  • Year and Date: 2016-04-06
  • Int'l Joint Research
• [Presentation] Placental phenotypes of Chst14 -/- fetal mice: a model for vascular manifestations in Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency (2016)
  • Author(s): Takahiro Yoshizawa, Shuji Mizumoto, Jun Nakayama, Takuya Hirose, Kazushige Takehana, Fengming Yue, Nana Tsumita, Chiaki Masuda, Yuko Kasahara, Yuki Takahashi, Shin-ichi Takeda, Takashi Okada, Kiyoshi Matsumoto, Tomoki Kosho
  • Organizer: The 13th International Congress of Human Genetics (ICHG2016)
  • Place of Presentation: 京都国際会館, 京都市, 京都府
  • Year and Date: 2016-04-04
  • Int'l Joint Research
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  • URL: http://www.shinshu-u.ac.jp/institution/hito/i-animal/index.html