[Frontiers in Bioscience 6, d222-238, February 1, 2001]

GENE TARGETING IN HEMOSTASIS. PROTHROMBIN

William Y. Sun and Sandra J. F. Degen

Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, OH 45229

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. The Biology of Prothrombin and Thrombin
2.2. The Structure of Prothrombin
2.3. The Gene Coding for Prothrombin
2.4. The Developmental and Tissue-Specific Pattern of Expression of Prothrombin and the PAR-1 Receptor
3. Results
3.1. Targeting Strategy
3.2. Generation of Prothrombin-deficient mice
3.3. Characterization of Prothrombin-deficient mice
3.4. Summary of Results Obtained by Others in the Generation of Prothrombin-deficient Mice
4. Perspective
5. Acknowledgments
6. References

1. ABSTRACT

There have been extensive studies on the structure and function of prothrombin; a protein critical for the coagulation of blood. The biological functions of prothrombin and its activated form, thrombin are discussed, as well as the structure and functional domains of the protein. Prothrombin is expressed in a tissue-specific manner and its gene structure and regulatory elements have been analyzed in detail. In order to learn more about the functions of prothrombin in an in vivo context, the gene was ablated in mice. Homozygous deletion of prothrombin results in a partial embryonic lethal phenotype. Approximately half of the homozygous mutant mice die during mid-gestation and the remainder die soon after birth. The cause of death of neonates is due to excessive bleeding, while null embryos have a lack of integrity of the yolk sac membrane resulting in bleeding into the yolk sac cavity. These results are discussed in relation to the phenotypes found for other mice lacking specific coagulation factors.