Gene analysis of a novel thrombotic risk factor; antithrombin-resistance.
Project/Area Number |
22590524
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Single-year Grants |
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(保健), 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(保健), 助教 (30135371)
|
Project Period (FY) |
2010 – 2012
|
Project Status |
Completed (Fiscal Year 2012)
|
Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
Keywords | 臨床血液学 / 静脈血栓塞栓症 / 先天性血栓性素因 / 遺伝子変異 / アンチトロンビン抵抗性 / 原因遺伝子変異 / アンチトロンビン欠損症 / プロテインC欠損症 / プロテインS欠損症 / アンチトロンビン抵抗性 / スクリ―ニング検査法 / アンチトロンビン欠損症 / プロテインC欠損症 / プロテインS欠損症 / スクリーニング検査法 |
Research Abstract |
Venous thromboembolism is a multifactorial disease resulting from a complex interaction between circumstantial and genetic factors. In this study, we investigated possible causative gene defects in a large Japanese family with inherited thrombophilia, and found a novel missense mutation in the prothrombin gene resulting in a variant prothrombin. The mutation located at one of the antithrombin (AT) binding sites of thrombin molecule. We prepared wild-type and mutant recombinant prothrombins, and compared by prothrombin activation, AT-binding, and thrombin generation assays. In thrombin-antithrombin complex (TAT) formation, the mutant thrombin was impareded to form TAT. In thrombin generation assay of reconstituted prothrombin-deficient plasma with recombinant prothrombins, the mutant showed a decreased peak thrombin and an increased endogenous thrombin potential. We identified a novel F2 mutation leading to the mutant AT-resistant thrombin, which could be a cause of the inherited thrombophilia in this family.
|
Report
(4 results)
Research Products
(65 results)
-
[Journal Article] Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation factor VII gene expression2013
Author(s)
Suzuki A, Miyawaki Y, Okuyama E, Murata M, Ando Y, Kato I, Takagi Y, Takagi A, Murate T, Saito H, Kojima T
-
Journal Title
Biochemical J
Volume: 449(1)
Pages: 231-239
Related Report
Peer Reviewed
-
-
[Journal Article] Comparison of the efficacy of ribavirin plus peginterferon alfa-2b for chronic hepatitis C infection in patients with and without coagulation disorders.2013
Author(s)
Honda T, Katano Y, Kuzuya T, Hayashi K, Ishigami M, Itoh A, Hirooka Y, Nakano I, Ishikawa T, Toyoda H, Kumada T, Yamamoto K, Matsushita T, Kojima T, Takamatsu J, Goto H
-
Journal Title
J Med Virol.
Volume: 85(2)
Issue: 2
Pages: 228-234
DOI
Related Report
Peer Reviewed
-
[Journal Article] A possible mechanism for Inv22-related F8 large deletions in severe hemophilia a patients with high responding factor VIII inhibitors2012
Author(s)
Fujita J, Miyawaki Y, Suzuki A, Maki A, Okuyama E, Murata M, Takagi A, Murate T, Suzuki N, Matsushita T, Saito H, Kojima T
-
Journal Title
J Thromb Haemost
Volume: 10(10)
Pages: 2099-2107
Related Report
Peer Reviewed
-
-
-
[Journal Article] Thrombosis from a prothrombin mutation conveying antithrombin resistance2012
Author(s)
Miyawaki Y, Suzuki A, Fujita J, Maki A, Okuyama E, Murata M, Takagi A, Murate T, Kunishima S, Sakai M, Okamoto K, Matsushita T, Naoe T, Saito H, Kojima K
-
Journal Title
N Engl J Med
Volume: 366
Pages: 2390-2396
Related Report
Peer Reviewed
-
[Journal Article] A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiectasia.2012
Author(s)
Suzuki A, Nakashima D, Miyawaki Y, Fujita J, Maki A, Fujimori Y, Takagi A, Murate T, Teranishi M, Matsushita T, Saito H, Kojima T
-
Journal Title
Thromb Res
Volume: 129(5)
Related Report
Peer Reviewed
-
-
[Journal Article] Thrombosis from a prothrombin mutation conveying antithrombin resistance.2012
Author(s)
Miyawaki Y, Suzuki A, Fujita J, Maki A, Okuyama E, Murata M, Takagi A, Murate T, Kunishima S, Sakai M, Okamoto K, Matsushita T, Naoe T, Saito H, Kojima T
-
Journal Title
N Engl J Med.
Volume: 366
Issue: 25
Pages: 2390-2396
DOI
Related Report
Peer Reviewed
-
-
[Journal Article] Syndecan-4 Regulates Early Neutrophil Migration and Pulmonary Inflammation in Response to Lipopolysaccharide.2012
Author(s)
Tanino Y, Chang MY, Wang X, Gill SE, Skerrett S, McGuire JK, Sato S, Nikaido T, KojimaT, Munakata M, Mongovin S, Parks WC, Martin TR, Wight TN, Charles W
-
Journal Title
Am J Respir Cell Mol Biol.
Volume: 47(2)
Issue: 2
Pages: 196-202
DOI
Related Report
Peer Reviewed
-
-
-
[Journal Article] Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans2011
Author(s)
Iwaki T, Tanaka A, Miyawaki Y, Suzuki A, Kobayashi T, Takamatsu J, Matsushita T, Umemura K, Urano T, Kojima T, Terao T, Kanayama N
-
Journal Title
J Thromb Haemost
Volume: 9(6)
Pages: 1200-6
Related Report
Peer Reviewed
-
[Journal Article] Syndecan-4 deficiency limits neointimal formation after vascular injury by regulating vascular smooth muscle cell proliferation and vascular progenitor cell mobilization.2011
Author(s)
Ikesue M, Matsui Y, Ohta D, Danzaki K, Ito K, Kanayama M, Kurotaki D, Morimoto J, Kojima T, Tsutsui H, Uede T
-
Journal Title
Arterioscler Thromb Vasc Biol
Volume: 31(5)
Pages: 1066-74
Related Report
Peer Reviewed
-
-
[Journal Article] Virus-Associated Hemophagocytic Syndrome Caused by Pandemic Swine-Origin Influenza A (H1N1) in a Patient After Unrelated Bone Marrow Transplantation2011
Author(s)
A Katsumi, T Nishida, M Murata, S Terakura, K Shimada, S Saito, M Kobayashi, A Kodaira, S Shibata, I Oda, T Yagi, H Kiyoi, T Matsushita, T Kojima, T Naoe
-
Journal Title
Journal of Clinical and Experimental Hematopathology
Volume: 51
Issue: 1
Pages: 63-65
DOI
NAID
ISSN
1346-4280, 1880-9952
Related Report
Peer Reviewed
-
-
-
[Journal Article] Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans2011
Author(s)
T Iwaki, A Tanaka, Y Miyawaki, A Suzuki, T Kobayashi, J Takamatsu, T Matsushita, K Umemura, T Urano, T Kojima, T Terao, N Kanayama
-
Journal Title
J Thromb Haemost
Volume: 9(6)
Issue: 6
Pages: 1200-1206
DOI
Related Report
Peer Reviewed
-
-
-
[Journal Article] A novel splice site mutation in intron C of PROS1 leads to markedly reduced mutant mRNA level, absence of thrombin-sensitive region, and impaired secretion and cofactor activity of mutant protein S.2010
Author(s)
H Okada, S Kunishima, M Hamaguchi, A Takagi, K Yamamoto, J Takamatsu, T Matsushita, H Saito, T Kojima, T Yamazaki
-
Journal Title
Thromb Res
Volume: 125(5)
Related Report
Peer Reviewed
-
-
[Journal Article] Severe hemophilia A in a Japanese female caused by an F8-intron 22 inversion associated with skewed X chromosome inactivation2010
Author(s)
Y Miyawaki, A Suzuki, Y Fujimori, A Takagi, T Murate, N Suzuki, A Katsumi, T Naoe, K Yamamoto, T Matsushita, J Takamatsu, T Kojima
-
Journal Title
Int J Hematol
Volume: 92(2)
Pages: 405-408
NAID
Related Report
Peer Reviewed
-
-
-
-
[Presentation] Up-regulation mechanisms of syndecan-4, a heparan sulfate proteoglycan, expression by TNF-a in human endothelial like EAhy926 cells2012
Author(s)
Okuyama E, Murata M, Suzuki A, Ando Y, Kato I, Takagi Y, Takagi A, Murate T, Saito T, Kojima T
Organizer
第35回日本分子生物学会年
Place of Presentation
福岡
Related Report
-
[Presentation] A Possible Mechanism for Inv22-related F8 Large Deletions in Severe Hemophilia A Patients with High Responding Factor VIII Inhibitors2012
Author(s)
Fujita J, Miyawaki Y, Suzuki A, Okuyama E, Murata M, Ando Y, Kato I, Takagi Y, Hosaka M, Takagi A, Murate T, Kajiura Y, Suzuki N, Matsushita T, Saito T, Kojima T
Organizer
VIIth Congress of the Asian-Pacific Society on Thrombosis and Hemostasis
Place of Presentation
Melbourne, Australia
Related Report
-
[Presentation] Molecular Basis of Coagulation Factor IX Gene Abnormalities in 16 Japanese Hemophilia B Patients2012
Author(s)
Murata M, Okuyama E, Suzuki A, Miyawaki Y, Ando Y, Kato I, Takagi Y, Hosaka M, Takagi A, Murate T, Kishimoto, M, Suzuki N, Matsushita T, Saito T, Kojima T
Organizer
VIIth Congress of the Asian-Pacific Society on Thrombosis and Hemostasis
Place of Presentation
Melbourne, Australia
Related Report
-
[Presentation] NF-kappaB is essential for Syndecan-4 up-regulation by TNF-alpha in Vascular Endothelial-like EAhy926 Cells2012
Author(s)
Okuyama E, Murata M, Suzuki A, Miyawaki Y, Ando Y, Kato I, Takagi Y, Takagi A, Murate T, Saito T, Kojima T
Organizer
VIIth Congress of the Asian-Pacific Society on Thrombosis and Hemostasis
Place of Presentation
Melbourne, Australia
Related Report
-
[Presentation] Immunosuppressant IMP dehydrogenase inhibitors up-regulated coagulation factor VII mRNA2012
Author(s)
Suzuki A, Miyawaki Y, Okuyama E, Murata M, Ando Y, Kato I, Takagi Y, Takagi A, Murate T, Saito T, Kojima T
Organizer
第74回日本血液学会学術集会
Place of Presentation
京都
Related Report
-
[Presentation] Molecular mechanisms of syndecan-4 upregulation by TNF-. in the endothelial-like EAhy926 cells2012
Author(s)
Okuyama E, Murata M, Ando Y, Kato I, Takagi Y, Miyawaki Y, Suzuki A, Takagi A, Murate T, Saito T, Kojima T
Organizer
第74回日本血液学会学術集会
Place of Presentation
京都
Related Report
-
[Presentation] A Possible Mechanism for Inv22-related F8 Large Deletions in Severe Hemophilia A Patients with High Responding Factor VIII Inhibitors.2012
Author(s)
Fujita J, Miyawaki Y, Suzuki A, Okuyama E, Murata M, Ando Y, Kato I, Takagi Y, Hosaka M, Takagi A, Murate T, Kajiura Y, Suzuki N, Matsushita T, Saito H, Kojima T
Organizer
VIIth Congress of the Asian-Pacific Society on Thrombosis and Hemostasis
Place of Presentation
Meibourun, Australia
Related Report
-
-
-
[Presentation] A NOVEL PROTHROMBIN GENE MUTATION LEADS TO AN AT-RESISTANT THROMBIN IN A FAMILY WITH INHERITED THROMBOPHILIA2011
Author(s)
Miyawaki Y, Suzuki A, Fujimori Y, Fujita J, Maki A, Takagi A, Murate T, Sakai M, Okamoto K, Matsushita T, Kojima T
Organizer
XXIIIrd Congress of International Society on Thrombosis and Haemostasis
Place of Presentation
Kyoto, Japan
Related Report
-
[Presentation] DISTINCT X-CHROMOSOMAL REARRANGEMENTS WITH F8-INTRON22 INVERSION IN THREE UNRELATED JAPANESE SEVERE HEMOPHILIA A PATIENTS WITH HIGH TITER INHIBITOR2011
Author(s)
Fujita J, Suzuki A, Miyawaki Y, Maki A, Fujimori Y, Takagi A, Murate T, Matsushita T, Suzuki N, Saito H, Kojima T
Organizer
XXIIIrd Congress of International Society on Thrombosis and Haemostasis
Place of Presentation
Kyoto, Japan
Related Report
-
-
-
[Presentation] OS-3-120: Molecular basis of an AT-resistant variant thrombin found in a Japanese family with thrombophilia2011
Author(s)
Miyawaki Y, Suzuki A, Fujita J, Maki A, Okuyama E, Murata M, Takagi A, Murate T, Kunishima S, Sakai M, Okamoto K, Matsushita T, Kojima T
Organizer
第73回日本血液学会学術集会
Place of Presentation
名古屋
Related Report
-
-
[Presentation] PS-1-72: Unusual X-chromosomal rearrangements with F8-int22 inversion in three severe hemophilia A patients2011
Author(s)
Fujita J, Miyawaki Y, Suzuki A, Maki A, Okuyama E, Murata M, Takagi A, Murate T, Matsushita T, Suzuki N, Saito H, Kojima T
Organizer
第73回日本血液学会学術集会
Place of Presentation
名古屋
Related Report
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-