Unveiling of the molecular pathogenesis of gelatinous drop-like dystrophy in a view of multimerization of claudin proteins

• Project/Area Number: 18K09446
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Osaka University
• Principal Investigator: Kawasaki Satoshi 大阪大学, 大学院医学系研究科, 特任准教授(常勤) (60347458)
• Co-Investigator(Kenkyū-buntansha): 辻川 元一 大阪大学, 大学院医学系研究科, 教授 (70419472)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 遺伝性角膜ジストロフィ / 膠様滴状角膜ジストロフィ / クローディン / タイトジャンクション

Outline of Final Research Achievements

GDLD is known to cause impaired tight junction function in corneal epithelial cells, but prior to this study, the mechanism by which loss-of-function mutations in the TACSTD2 gene lead to impaired tight junction function had not been clarified.
In this study, we show that the TACSTD2 gene and its paralogous gene, the EpCAM gene, are involved in the formation of claudin 1 and 7 oligomers, and that in the absence of the expression of TACSTD2 and EpCAM genes, claudins 1 and 7 form aggregates. This may be the primary mechanism for the impaired tight junction function in GDLD corneal epithelial cells.

Academic Significance and Societal Importance of the Research Achievements

膠様滴状角膜ジストロフィ(GDLD)は世界的にはまれな疾患であるが本邦では比較的見られる疾患である。それまでにGDLDにおいてタイトジャンクション機能が低下することは知られていたが、その詳細な分子病態は不明であった。本研究によってTACSTD2あるいはEpCAM遺伝子が発現しない状況ではクローディン1および7タンパクが多量体形成して凝集することが明らかとなった。凝集したクローディンタンパクは恐らく小胞体に関連した分解システムによって分解され、タイトジャンクション機能の低下につながるものと推察される。本邦で比較的みられるGDLDの分子病態がより詳細になったことで創薬などへの発展が期待できる。

Research Products

• [Journal Article] Corneal Opacity Induced by Light in a Mouse Model of Gelatinous Drop-Like Corneal Dystrophy (2020)
  • Author(s): Nagahara Y, Tsujikawa M, Koto R, Uesugi K, Sato S, Kawasaki S, Maruyama K, Nishida K.
  • Journal Title: The American Journal of Pathology Volume: 190 Issue: 12 Pages: 2330-2342
  • DOI: 10.1016/j.ajpath.2020.08.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Generation and validation of a PITX2-EGFP reporter line of human induced pluripotent stem cells enables isolation of periocular mesenchymal cells. (2020)
  • Author(s): Okubo T, Hayashi R, Shibata S, Kudo Y, Ishikawa Y, Inoue S, Kobayashi Y, Honda A, Honma Y, Kawasaki S, Nishida K.
  • Journal Title: J Biol Chem. Volume: 295 Issue: 11 Pages: 3456-3465
  • DOI: 10.1074/jbc.ra119.010713
  • Peer Reviewed / Open Access
• [Journal Article] Homeostasis of SLC4A11 protein is mediated by endoplasmic reticulum-associated degradation (2019)
  • Author(s): Hara Susumu、Tsujikawa Motokazu、Kawasaki Satoshi、Nishida Kohji
  • Journal Title: Experimental Eye Research Volume: 188 Pages: 107782-107782
  • DOI: 10.1016/j.exer.2019.107782
  • Peer Reviewed / Open Access
• [Journal Article] Conjunctival dysbiosis in mucosa-associated lymphoid tissue lymphoma. (2019)
  • Author(s): Asao K, Hashida N, Ando S, Motooka D, Kurakami H, Nakamura S, Yamashita D, Maruyama K, Kawasaki S, Yamada T, Iida T, Nishida K.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 8424-8424
  • DOI: 10.1038/s41598-019-44861-5
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of therapeutic soft contact lens in the management of gelatinous drop-like corneal dystrophy (2019)
  • Author(s): Maeno Sayo、Soma Takeshi、Tsujikawa Motokazu、Shigeta Ryujiro、Kawasaki Ryo、Oie Yoshinori、Koh Shizuka、Maruyama Kazuichi、Kawasaki Satoshi、Maeda Naoyuki、Nishida Kohji
  • Journal Title: British Journal of Ophthalmology Volume: 104 Issue: 2 Pages: 241-246
  • DOI: 10.1136/bjophthalmol-2018-313809
  • Peer Reviewed / Open Access
• [Journal Article] A New in Vitro Model of GDLD by Knocking Out TACSTD2 and Its Paralogous Gene EpCAM in Human Corneal Epithelial Cells (2018)
  • Author(s): Xu Peng、Kai Chifune、Kawasaki Satoshi、Kobayashi Yuki、Yamamoto Kouji、Tsujikawa Motokazu、Hayashi Ryuhei、Nishida Kohji
  • Journal Title: Translational Vision Science & Technology Volume: 7 Issue: 6 Pages: 30-30
  • DOI: 10.1167/tvst.7.6.30
  • Peer Reviewed / Open Access
• [Presentation] GENERATION OF AN IN VITRO DISEASE MODEL OF ANIRIDIA BY INTRODUCING HETEROZYGOUS LOSS-OF-FUNCTION MUTATION OF PAX6 GENE IN HUMAN IPS CELLS (2021)
  • Author(s): Satoshi Kawasaki , Kohji Ohmoto , Kohji Nishida
  • Organizer: International Society for Stem Cell Research
• [Presentation] 膠様滴状角膜ジストロフィでの治療用ソフトコンタクトレンズ装用と細菌性角膜炎の検討 (2019)
  • Author(s): 前野紗代，辻川元一，繁田龍二郎，大家義則，相馬剛至，高静花，川崎諭，前田直之，西田幸二
  • Organizer: 第62回日本コンタクトレンズ学会総会
• [Presentation] The phenotype of knockout mouse of tumor-associated calcium signal transducer2 as a model of gelatinous drop-like corneal dystrophy. (2019)
  • Author(s): Yukiko Nagahara, k. uesugi, P. Xu, S. Kawasaki, M. Tsujikawa, K. Nishida.
  • Organizer: ARVO Annual Meeting 2019