Molecular elucidation of antithrombin resistance mechanism and development of thrombophilia model mouse.

2015 Fiscal Year Final Research Report

• Project/Area Number: 25293129
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Nagoya University
• Principal Investigator: Kojima Tetsuhito 名古屋大学, 医学(系)研究科(研究院), 教授 (40161913)
• Co-Investigator(Kenkyū-buntansha): MATSUSHITA Tadashi 名古屋大学, 医学部附属病院, 教授 (30314008) ; TAKAGI Akira 名古屋大学, 大学院医学系研究科, 准教授 (30135371)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: アンチトロンビン-レジスタンス（ATR） / プロトロンビン異常症 / トロンビン / 遺伝性血栓症 / 一塩基置換 / トロンボモジュリン / R593Lプロトロンビン-ノックインマウス / 相同組換え

Outline of Final Research Achievements

We established a laboratoly test to detect antithromnbin resistance (ATR) in plasma, identified Serbia mutation (p.R596Q) using this method, and newly found 2 distinct Japanese families with ATR caused by Serbian mutation. We reported one of them as the first Japanese thrombophilia family associated with Serbian ATR mutation. In addition, we revealed that mutant thrombin derived from prothrombin Yukuhasi conveying ATR showed thrombomodulin resistance (TMR), in termas of fibrinogen clotting inhibition. Single-base substitution missense variants at 596R of the prothrombin induced ATR and TMR. Furthermore, we established a heterozygous R593L (correspond to R596L in human) knock-in mouse, and observed that 14 out of 40 new born mouse pups in the breeding of the heterozygous mice soon died, suggesting new born lethality of homozygous R593L knock-in mouse.

Free Research Field

血液内科、病態検査学