Thrombomodulin Gene Defects in Families with Thromboembolic Disease – A Report on Four Families

Ann-Kristin Öhlin; Richard A. Marlar

doi:10.1055/s-0037-1614473

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1999; 81(03): 338-344
DOI: 10.1055/s-0037-1614473

Review Article

Schattauer GmbH

Thrombomodulin Gene Defects in Families with Thromboembolic Disease – A Report on Four Families

Authors

Ann-Kristin Öhlin

¹From the Institute of Laboratory Medicine, Department of Clinical Chemistry, University Hospital, Lund, Sweden and, Denver, Colorado, USA
Richard A. Marlar

²Department of Pathology, University of Colorado School of Medicine and Laboratory Services, Denver Veterans Affairs Medical Center, Denver, Colorado, USA

Abstract

Summary

It has been suggested that an impaired thrombomodulin (TM) function could constitute an abnormality leading to thromboembolic disease (TED). The TM gene from 51 unrelated American patients with TED and 100 American blood donors was screened for mutations. Four heterozygous point mutations in the TM gene were detected. The mutations are distributed throughout the TM gene and predict amino acid changes 1) Pro⁴⁸³ to Leu, 2) Gly⁶¹ to Ala, 3) Asp⁴⁶⁸ to Tyr (earlier described) and 4) a silent mutation not predicting any amino acid change at Glu¹⁶³. Family studies reveal that the occurrence of the different TM mutations is associated with a history of TED, but there are indications of multiple risk factors and no perfect co-segregation of the TM defects and TED. Among the controls, three individuals carried heterozygous TM variants predicting either a Pro⁴⁷⁷-Ser mutation (two cases) or an Asp⁴⁶⁸-Tyr mutation. Our results thus demonstrate that a previously undocumented abnormality in the protein C anticoagulant pathway, a defect in the TM gene, to a certain extent co-segregates with familial thrombophilia. Further studies are needed to prove the causality of these TM mutations.

Volltext

Referenzen

References
1 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477-80.
2 Esmon CT. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost 1993; 70: 29-35.
3 Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 1995; 9: 946-55.
4 Raife TJ, Lager DJ, Madison KC, Piette WW, Howard EJ, Sturm MT, Chen Y, Lentz SR. Thrombomodulin expression by human keratinocytes. J Clin Invest 1994; 93: 1846-51.
5 Healy AM, Rayburn HB, Rosenberg RD, Weiler H. Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci 1995; 92: 850-4.
6 Takono S, Kimura S, Ohdama S, Aoli N. Plasma thrombomodulin in health and diseases. Blood 1990; 76 10: 2024-9.
7 Ishii H, Majerus PW. Thrombomodulin is present in human plasma and urine. J Clin Invest 1985; 76: 2178-81.
8 Nachman RL, Silverstein R. Hypercoagulable states. Ann Intern Med 1993; 119: 819-27.
9 Svensson PJ, Dahlbäck B. Resistance to activated Protein C as a basis or venous thrombosis. N Engl J Med 1994; 330 (08) 517-22.
10 Öhlin A-K, Marlar RM. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood 1995; 85 (02) 330-6.
11 Ireland H, Kunz G, Kyriakoulis K, Stubbs PJ, Lane D. Thrombomodulin gene mutations associated with myocardial infarction. Circulation 1997; 96 (01) 15-8.
12 Öhlin A-K, Morser J, Öhlin H. Soluble thrombomodulin antigen in plasma is increased in patients with acute myocardial infarction treated with thrombolytic therapy. Thromb Res 1996; 82 (04) 313-22.
13 van der Velden PA, Krommenhoek-Van Es T, Allaart CF, Bertina RM, Reitsma PH. A frequent thrombomodulin amino acid dimorphism is not associated with thrombophilia. Thromb Haemost 1991; 65: 511-3.
14 Lane DA, Mannuci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76 (05) 651-62.
15 Lane DA, Mannuci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 2. Thromb Haemost 1996; 76 (06) 824-34.
16 Honda G, Masaki C, Zushi M, Tsuruta K, Sata M, Mohri M, Gomi K, Kondo S, Yamamoto S. The roles played by the D2 and D3 domains of recombinant human thrombomodulin in its function. J Biochem 1995; 118: 1030-6.
17 Conrad M, Friedlander C, Goodman M. Evidence that natural selection acts on silent mutation. Biosystems 1983; 16: 101-11.
18 Conway EM, Pollefeyt S, Collen D, Steiner-Mosony M. The amino terminal lectin-like domain of thrombomodulin is required for constitutive endocytosis. Blood 1997; 89 (02) 652-61.
19 Öhlin A-K, Norlund L, Marlar R. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost 1997; 78 (01) 396-400.
20 Norlund L, Zöller B, Öhlin A-K. A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis. Thromb Haemost 1997; 78: 1164-6.
21 Norlund L, Holm J, Zöller B, Öhlin A-K. An arterial thrombus associated with a silent thrombomodulin gene mutation. Submitted.
22 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: Pathogenesis, clinical syndromes, and management. Blood 1996; 87 (09) 3531-44.
23 Norlund L, Holm J, Zöller B, Öhlin A-K. A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost 1997; 77 (02) 248-51.
24 Faioni EM, Merati G, Peyvandi F, Bettini PM, Mannucci PM. The G1456 to T mutation in the thrombomodulin gene is not frequent in patients with venous thrombosis. Blood 1997; 89 (04) 1467.
25 Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K. Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. J Biochem 1988; 103: 281-5.