Fuyong Zhang1, Ying Gui2, Yu Lu3, Denghe Liu1, Huaping Chen1, Xue Qin1, Shan Li4. 1. Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, No.6 of Shuangyong Road, Nanning 530021, Guangxi, China. 2. Clinical Laboratory Center, The First Affiliated Hospital of Guangxi Medical University, No.6 of Shuangyong Road, Nanning 530021, Guangxi, China. 3. Department of Clinical Laboratory, Liuzhou People's Hospital, No.8 of Wenchang Road, Liuzhou 545000, Guangxi, China. 4. Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, No.6 of Shuangyong Road, Nanning 530021, Guangxi, China. Electronic address: lis8858@126.com.
Abstract
BACKGROUND: Antithrombin (AT) is the primary physiological anticoagulant of normal hemostasis. Hereditary AT deficiency, an autosomal dominant thrombotic disease caused by mutations in the AT gene (SERPINC1), is associated with venous thromboembolism. OBJECTIVE: We investigated the phenotypes, genotypes, and pathogenesis of hereditary AT deficiency in a 12-year-old boy (proband) who developed a pulmonary embolism and a subsequent deep vein thrombosis. METHODS: The AT activity and AT antigen level of the proband and his family members were measured. Mutation sites in all seven exons of SERPINC1 were identified. Analysis of conserved regions around codon 462 of the SERPINC1 gene and functional predictions were performed using bioinformatics tools. RESULTS: The proband, his father, and his paternal grandmother demonstrated reduced AT activity and antigen levels consistent with Type I AT deficiency. A novel heterozygous missense mutation, c.1385G>A (Cys462Tyr) was identified in all three symptomatic family members. This missense mutation causes disruption of the 279Cys-462Cys disulfide bond and leads to type Ⅰ hereditary AT deficiency. CONCLUSION: A SERPINC1 missense mutation (Cys462Tyr) causing damage to the 279Cys-462Cys disulfide bond of the AT protein appears to be the cause of Type I AT deficiency in this family. These findings indicate one pathological mechanism associated with hereditary AT deficiency.
BACKGROUND:Antithrombin (AT) is the primary physiological anticoagulant of normal hemostasis. Hereditary AT deficiency, an autosomal dominant thrombotic disease caused by mutations in the AT gene (SERPINC1), is associated with venous thromboembolism. OBJECTIVE: We investigated the phenotypes, genotypes, and pathogenesis of hereditary AT deficiency in a 12-year-old boy (proband) who developed a pulmonary embolism and a subsequent deep vein thrombosis. METHODS: The AT activity and AT antigen level of the proband and his family members were measured. Mutation sites in all seven exons of SERPINC1 were identified. Analysis of conserved regions around codon 462 of the SERPINC1 gene and functional predictions were performed using bioinformatics tools. RESULTS: The proband, his father, and his paternal grandmother demonstrated reduced AT activity and antigen levels consistent with Type I AT deficiency. A novel heterozygous missense mutation, c.1385G>A (Cys462Tyr) was identified in all three symptomatic family members. This missense mutation causes disruption of the 279Cys-462Cys disulfide bond and leads to type Ⅰ hereditary AT deficiency. CONCLUSION: A SERPINC1 missense mutation (Cys462Tyr) causing damage to the 279Cys-462Cys disulfide bond of the AT protein appears to be the cause of Type I AT deficiency in this family. These findings indicate one pathological mechanism associated with hereditary AT deficiency.