GENETIC STUDY OF PROTEIN C DEFICIENCY AND THROMBOSIS

该项目的目的是更好地了解与血液凝固有关的依赖维生素K的血浆蛋白的生物合成、激活和功能特性，以及这些蛋白突变对遗传性血栓形成的影响。这个项目通过对蛋白C突变的研究，特别探索了这些蛋白在参与与钙离子相关的过程之前被修饰、运输和分泌的基本机制。该项目的另一个方向是对可能的第二个基因THROMC进行染色体定位和鉴定，该基因与美洲原住民的一个I型蛋白C缺乏的大家族的血栓性疾病有关。其具体目的是在表现出血栓形成的家族中识别新的蛋白C突变；构建、表达和生化表征自然发生的分泌型和非分泌型蛋白C突变形式；以及通过遗传连锁分析确定与血栓形成相关的第二基因(THROMC)的存在和位置。对于血栓性疾病和血栓前状态的几个临床标志物，包括蛋白C、凝血酶原片段1.2和纤维蛋白D-二聚体水平，家庭成员也被分型。有或没有蛋白C缺乏的不相关的嗜血栓家系也被检查THROMC与疾病的关联。在报告所述期间12/1/97-11/30/98，我们在GCRC采集了5个蛋白C缺陷家系成员的全血和血浆样本。来自居住在其他地理位置的26名家庭成员的样本也被获取，但不是在GCRC。这项研究的家庭成员总数目前为328人。在整个研究期间，我们会继续使用GCRC从居住在附近的家庭成员那里获取血液样本。

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.