GENETIC STUDY OF PROTEIN C DEFICIENCY AND THROMBOSIS

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The objective of this project is to better understand the biosynthesis, activation, and functional properties of the vitamin K-dependent plasma proteins involved in blood clotting and the consequences of mutations in the proteins on hereditary thrombosis. This project specifically explores, through the study of protein C mutations, the fundamental mechanisms by which these proteins are modified, transported, and secreted prior to their involvement in Ca2+-membrane associated processes. Another direction of the project is the chromosomal localization and identification of a putative second gene, THROMC, that is associated with thrombotic disease in a large type I protein C deficient kindred of Native American decent. Specific aims are to identify new protein C mutations in families exhibiting thrombophilia; construct, express, and biochemically characterize secreted and non-secreted naturally occurring mutant forms of protein C; and determine by genetic linkage analysis the existence and location of a second gene (THROMC) associated with thrombosis. Family members are also phenotyped in regard to thrombotic disease and several clinical markers of the prothrombotic state, including protein C, prothrombin fragment 1.2, and fibrin D-dimer levels. Unrelated thrombophilic families with and without protein C deficiency are also examined for the association of THROMC with disease. During the reporting period 12/1/97 - 11/30/98, at the GCRC we obtained whole blood and plasma samples from 5 members of the protein C deficient kindred. Samples from 26 family members who live in other geographic locations were also obtained, but not at the GCRC. The total number of family members included in the study is now 328. We will continue using the GCRC to obtain blood samples from family members living near here throughout the study period.